Determining an Amount of Reperfusion in Myocardium and Assessing Effectiveness of Thrombolysis

ABSTRACT

Quantitatively determining an amount of reperfusion in an artery after angioplasty and quantitatively assessing an effectiveness of thrombolysis by non-invasively sensing from outside the subject mechanical vibrations from a mechanical contraction of at least one ventricle to simultaneously measure (a) IVCT (time duration of an isovolumetric contraction portion of a systole phase) and (b) a peak endocardial acceleration (PEA) during the IVCT. PEA is measured before and after opening the artery (or before and after thrombolysis) and in some embodiments one calculates a myocardial contractility index (MCI) of the subject, for example MCI=PEA/IVCT. A determination unit compares the first and second PEA (or the first and second MCI), and then determines an amount of reperfusion based on the comparison. The amount of reperfusion is proportionate to a viable myocardium and, in the case of thrombolysis, the amount of reperfusion quantitatively assesses the effectiveness of thrombolysis.

FIELD AND BACKGROUND OF THE INVENTION

The invention is in the field of medical diagnosis of cardiac problems.

After a heart attack, a common procedure is to open the coronary arterythrough angioplasty. An ECG can identify a location of cardiac damagebut not quantify it. Even invasively opening an artery in the heartthrough urgent angioplasty cannot determine the extent to which themyocardium has died. One problem is determining quantitatively theamount of reperfusion that has occurred in the myocardium after openingthe coronary artery after the heart attack as well as determining theamount of restoration of function in the subject's heart after the heartattack. A parallel problem is determining, after the artery has beenopened, an amount of viable or salvageable heart muscle after a heartattack occurs. Even after opening the cardiac artery one cannotdetermine the extent that the heart muscle has died and quantifying theseverity of a heart attack (i.e. severe, moderate, light). Knowing thisaffects prognosis and treatment for the patient. A further problem isdeciding when to discontinue administration of thrombolysis, especiallybased on a quantitative determination.

In addition, when a patient goes to the emergency room reporting chestpain, an ECG and a cardiac enzyme test are performed. It is widelyrecognized, however, that normal ECG and negative enzyme test resultswill result in 24 hour patient hospitalization as a precaution. Since80% of patients who report to the hospital emergency room with chestpain have chest pain that is not cardiac related, current clinicalpractice results in many unnecessary hospitalizations.

There is therefore a compelling need to have improved methods,apparatuses and/or systems for accurate diagnosis of cardiac relatedchest pain and there is a compelling need to have accurate diagnosticsfor other cardiac related issues.

SUMMARY OF THE INVENTION

One aspect of the invention is a non-invasive apparatus configured tonon-invasively determine an amount of reperfusion of blood to amyocardium supplied by an artery of a mammalian subject after a heartattack of the mammalian subject, the apparatus comprising a sensor unitconfigured to non-invasively sense from outside the subject mechanicalvibrations that are from a mechanical contraction of at least one of theventricles of the heart of the mammalian subject so as to simultaneouslymeasure (a) IN/CT, wherein IVCT is a time duration of an isovolumetriccontraction portion of a systole phase of a cardiac cycle of thesubject; and (b) a peak endocardial acceleration (PEA) of the heart ofthe subject during the IVCT; and a determination unit comprising one ormore processors programmed by software stored on a memory, thedetermination unit configured to receive digital signals correspondingto the sensed mechanical vibrations, and to determine the PEA during theIVCT, the determination unit including a perfusion module fordetermining, by the one or more processors, an amount of reperfusion inthe myocardium by comparing a first PEA of the subject sensed by thesensor unit after a heart attack but before opening the artery to asecond PEA of the subject sensed by the sensor unit at a subsequent timeafter opening the artery, said amount of reperfusion being proportionateto a viable myocardium supplied by the artery.

Another aspect of the invention is a method of non-invasivelydetermining an amount of reperfusion in a myocardium supplied by anartery of a mammalian subject after a heart attack of the mammaliansubject, comprising after a heart attack but before opening the arterynon-invasively sensing by a device positioned outside the subjectmechanical vibrations that are from a mechanical contraction of at leastone of the ventricles of the heart of the mammalian subject, so as tomeasure a first peak endocardial acceleration (PEA) of the heart of thesubject during an IVCT wherein IVCT is a time duration of anisovolumetric contraction portion of a systole phase of a cardiac cycleof the subject; after opening the artery after the heart attack,non-invasively sensing by a device positioned outside the subjectmechanical vibrations that are from a mechanical contraction of at leastone of the ventricles of the heart of the mammalian subject, so as tomeasure a second peak endocardial acceleration (PEA) of the heart of thesubject during an IVCT; and determining, by one or more processors, anamount of reperfusion in the myocardium by comparing an amount by whichthe second PEA exceeds the first PEA, said amount of reperfusion beingproportionate to a viable myocardium supplied by the artery.

A still further aspect of the invention is a non-invasive apparatusconfigured to non-invasively determine an amount of reperfusion of bloodto a myocardium supplied by an artery of a mammalian subject after aheart attack of the mammalian subject, the apparatus comprising a sensorunit configured to non-invasively sense from outside the subjectmechanical vibrations that are from a mechanical contraction of at leastone of the ventricles of the heart of the mammalian subject so as tosimultaneously measure (a) IVCT, wherein IVCT is a time duration of anisovolumetric contraction portion of a systole phase of a cardiac cycleof the subject; and (b) a peak endocardial acceleration (PEA) of theheart of the subject during the IVCT; and a determination unitcomprising one or more processors programmed by software stored on amemory, the determination unit configured to receive digital signalscorresponding to the sensed mechanical vibrations, and to determine thePEA during the IVCT, the one or more processors configured to alsocalculate a first myocardial contractility index (MCI) of the subjectsuch that MCI comprises a ratio of the PEA of the subject to the IVCT ofthe subject; the determination unit including a perfusion module fordetermining, by the one or more processors, an amount of reperfusion inthe myocardium by comparing a first MCI of the subject sensed by thesensor unit after a heart attack but before opening the artery to asecond MCI of the subject sensed by the sensor unit at a subsequent timeafter opening the artery, said amount of reperfusion being proportionateto a viable myocardium supplied by the artery.

Another aspect of the invention is a method of non-invasivelydetermining an amount of reperfusion in a myocardium supplied by anartery of a mammalian subject after a heart attack of the mammaliansubject, comprising after a heart attack but before opening the arterynon-invasively sensing by a device positioned outside the subjectmechanical vibrations that are from a mechanical contraction of at leastone of the ventricles of the heart of the mammalian subject, so as tosimultaneously measure a first IVCT, wherein IVCT is a time duration ofan isovolumetric contraction portion of a systole phase of a cardiaccycle of the subject, and a first peak endocardial acceleration (PEA) ofthe heart of the subject during the first IVCT; calculating, by one ormore processors, a first myocardial contractility index (MCI) of thesubject, wherein the first MCI comprises a ratio of the first PEA of thesubject to the first IVCT of the subject; after opening the artery afterthe heart attack, non-invasively sensing by a device positioned outsidethe subject mechanical vibrations that are from a mechanical contractionof at least one of the ventricles of the heart of the mammalian subject,so as to simultaneously measure a second IVCT and a second peakendocardial acceleration (PEA) of the heart of the subject during thesecond IVCT; calculating, by one or more processors, a second myocardialcontractility index (MCI) of the subject wherein the second MCIcomprises a ratio of the second PEA of the subject to the second IVCT ofthe subject; and determining, by one or more processors, an amount ofreperfusion in the myocardium, by comparing an amount by which thesecond MCI exceeds the first MCI, said amount of reperfusion beingproportionate to a viable myocardium supplied by the artery.

A still further aspect of the invention is a non-invasive apparatusconfigured to non-invasively assess an effectiveness of thrombolysis ona clot in an artery of a mammalian subject after a heart attack of themammalian subject by determining an amount of reperfusion in the artery,the apparatus comprising a sensor unit configured to non-invasivelysense from outside the subject mechanical vibrations that are from amechanical contraction of at least one of the ventricles of the heart ofthe mammalian subject so as to simultaneously measure (a) IVCT, whereinIVCT is a time duration of an isovolumetric contraction portion of asystole phase of a cardiac cycle of the subject; and (b) a peakendocardial acceleration (PEA) of the heart of the subject during theIVCT; and a determination unit comprising one or more processorsprogrammed by software stored on a memory, the determination unitconfigured to receive digital signals corresponding to the sensedmechanical vibrations, and to determine the PEA during the IVCT, thedetermination unit including a perfusion module for determining, by theone or more processors, an amount of reperfusion in the artery bycomparing a first PEA of the subject sensed by the sensor unit after aheart attack but before the thrombolysis to a second PEA of the subjectsensed by the sensor unit after the thrombolysis, said amount ofreperfusion determining an assessment of the effectiveness of thethrombolysis.

Another aspect of the invention is a method of non-invasively assessingan effectiveness of thrombolysis on a clot in an artery of a mammaliansubject after a heart attack of the mammalian subject by determining anamount of reperfusion in the artery, comprising after a heart attack butbefore thrombolysis, non-invasively sensing by a device positionedoutside the subject mechanical vibrations that are from a mechanicalcontraction of at least one of the ventricles of the heart of themammalian subject, so as to measure a first peak endocardialacceleration (PEA) of the heart of the subject during an IVCT whereinIVCT is a time duration of an isovolumetric contraction portion of asystole phase of a cardiac cycle of the subject; after the thrombolysisto dissolve the clot, non-invasively sensing by a device positionedoutside the subject mechanical vibrations that are from a mechanicalcontraction of at least one of the ventricles of the heart of themammalian subject, so as to measure a second peak endocardialacceleration (PEA) of the heart of the subject during an IVCT; anddetermining, by one or more processors, an amount of reperfusion in theartery by comparing an amount by which the second PEA exceeds the firstPEA, said amount of reperfusion determining an assessment of theeffectiveness of the thrombolysis.

A further aspect of the invention is a non-invasive apparatus configuredto non-invasively assess an effectiveness of thrombolysis on a clot inan artery of a mammalian subject after a heart attack of the mammaliansubject by determining an amount of reperfusion in the artery, theapparatus comprising a sensor unit configured to non-invasively sensefrom outside the subject mechanical vibrations that are from amechanical contraction of at least one of the ventricles of the heart ofthe mammalian subject so as to simultaneously measure (a) IVCT, whereinIVCT is a time duration of an isovolumetric contraction portion of asystole phase of a cardiac cycle of the subject; and (b) a peakendocardial acceleration (PEA) of the heart of the subject during theIVCT; and a determination unit comprising one or more processorsprogrammed by software stored on a memory, the determination unitconfigured to receive digital signals corresponding to the sensedmechanical vibrations, and to determine the PEA during the IVCT, the oneor more processors configured to also calculate a first myocardialcontractility index (MCI) of the subject such that MCI comprises a ratioof the PEA of the subject to the IVCT of the subject; the determinationunit including a perfusion module for determining, by the one or moreprocessors, an amount of reperfusion in the artery by comparing a firstMCI of the subject sensed by the sensor unit after a heart attack butbefore the thrombolysis to a second MCI of the subject sensed by thesensor unit after the thrombolysis, said amount of reperfusiondetermining an assessment of the effectiveness of the thrombolysis.

A still further aspect of the invention is a method of non-invasivelyassessing an effectiveness of thrombolysis on a clot in an artery of amammalian subject after a heart attack of the mammalian subject bydetermining an amount of reperfusion in the artery, comprising after aheart attack but before thrombolysis, non-invasively sensing by a devicepositioned outside the subject mechanical vibrations that are from amechanical contraction of at least one of the ventricles of the heart ofthe mammalian subject, so as to simultaneously measure a first IVCT,wherein IVCT is a time duration of an isovolumetric contraction portionof a systole phase of a cardiac cycle of the subject, and a first peakendocardial acceleration (PEA) of the heart of the subject during thefirst IVCT; calculating, by one or more processors, a first myocardialcontractility index (MCI) of the subject, wherein the first MCIcomprises a ratio of the first PEA of the subject to the first IVCT ofthe subject; after the thrombolysis to dissolve the clot, non-invasivelysensing by a device positioned outside the subject mechanical vibrationsthat are from a mechanical contraction of at least one of the ventriclesof the heart of the mammalian subject, so as to simultaneously measure asecond IVCT and a second peak endocardial acceleration (PEA) of theheart of the subject during the second IVCT; calculating, by one or moreprocessors, a second myocardial contractility index (MCI) of the subjectwherein the second MCI comprises a ratio of the second PEA of thesubject to the second IVCT of the subject; and determining, by one ormore processors, an amount of reperfusion in the artery by comparing anamount by which the second MCI exceeds the first MCI, said amount ofreperfusion determining an assessment of the effectiveness of thethrombolysis.

These and other features, aspects and advantages of the invention willbecome better understood with reference to the following drawings,descriptions and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments are herein described, by way of example only, withreference to the accompanying drawings, wherein:

FIG. 1 is a graph of an ROC curve with AUC for PEA discriminationability between ischemia related chest pain and non-ischemia relatedchest pain, in accordance with one embodiment of the invention;

FIG. 2 is a graph of an ROC curve with AUC for MCI discriminationability between ischemia related chest pain and non-ischemia relatedchest pain, in accordance with one embodiment of the invention;

FIG. 3A is a schematic view of an apparatus, which apparatus isconfigured to utilize MCI, a new parameter, in accordance with oneembodiment of the invention;

FIG. 3B is a schematic view of an apparatus, in accordance with oneembodiment of the invention;

FIG. 3C is a perspective view showing a sensor unit and an operationunit of an apparatus, which apparatus is configured to utilize MCI, anew parameter, in accordance with one embodiment of the invention;

FIG. 3D is a perspective view showing a sensor unit and an operationunit of an apparatus, in accordance with one embodiment of theinvention;

FIG. 3E shows a block diagram of an apparatus, in accordance with oneembodiment of the invention;

FIG. 4 is a flow chart showing a method, in accordance with oneembodiment of the invention;

FIG. 5 is a flow chart showing a further method, in accordance with oneembodiment of the invention;

FIG. 6 is a flow chart showing a still further method, in accordancewith one embodiment of the invention;

FIG. 7 is a flow chart showing a yet still further method, in accordancewith one embodiment of the invention;

FIG. 8 is a flow chart showing a still further method, in accordancewith one embodiment of the invention;

FIG. 8AA is a flow chart showing a still further method, in accordancewith one embodiment of the invention;

FIG. 9 is a flow chart showing a yet still further method, in accordancewith one embodiment of the invention;

FIG. 9AA is a flow chart showing a yet still further method, inaccordance with one embodiment of the invention;

FIG. 10 is a flow chart showing a further method, in accordance with oneembodiment of the invention;

FIG. 10AA is a flow chart showing a further method, in accordance withone embodiment of the invention;

FIG. 11 is a flow chart showing a yet still further method, inaccordance with one embodiment of the invention;

FIG. 11AA is a flow chart showing a yet still further method, inaccordance with one embodiment of the invention;

FIG. 12 is a flow chart showing a further method, in accordance with oneembodiment of the invention;

FIG. 13 is a flow chart showing a further method, in accordance with oneembodiment of the invention;

FIG. 14 shows an EXCEL file summary of the results of the 27 subjectsenrolled in the study conducted in accordance with one embodiment of theinvention;

FIG. 15 is a graph of an analog signal of mechanical vibrations from themechanical contraction of at least one ventricle obtained by a sensorunit, in accordance with one embodiment of the invention;

FIG. 16 is a graph of two analog signals of a single patient obtained bya sensor unit, including an ECG signal and an analog signal ofmechanical vibrations from the mechanical contraction of at least oneventricle, in accordance with one embodiment of the invention; and

FIG. 17 is a graph showing three analog signals of a single patientobtained by a sensor unit, wherein the top signal is an ECG signal, thebottom signal is a microphone signal and the middle signal is ofmechanical vibrations from the mechanical contraction of at least oneventricle of the patient, in accordance with one embodiment of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description is of the best currently contemplatedmodes of carrying out the invention. The description is not to be takenin a limiting sense, but is made merely for the purpose of illustratingthe general principles of the invention.

The invention generally provides methods, apparatus and/or systems formedical diagnosis of cardiac issues in a mammalian subject, for examplea human, including but not limited to determining a quantitative amountof reperfusion in the myocardium after opening the artery, such as byangioplasty, a quantitative assessment of the amount of restoration offunction of the heart after opening the artery, a quantitativeassessment of the effectiveness of thrombolysis (for example whether ornot it has been effective in order to decide if it (i.e. medication) canbe discontinued) based on an amount of reperfusion in the artery, anamount of viable or salvageable myocardium that remains after a heartattack. The invention also provides methods, apparatus and/or systems ofquantitatively differentially diagnosing between cardiac related andnon-cardiac related chest pain in a mammalian subject, for example ahuman, including in some embodiments doing so dynamically; determining,for example quantitatively, if total occlusion of an artery, for examplea coronary artery, has occurred, quantitatively determining myocardialinfarction. The invention uses in some embodiments a new parametercalled a myocardial contractility index (MCI) that in some embodimentscomprises a ratio of the Peak Endocardial Acceleration (PEA) of thesubject to the IVCT of the subject. In one embodiment, MCI=PEA/IVCT.

One problem in cardiology is determining the amount of viable orsalvageable heart muscle after a heart attack occurs. Another relatedproblem is quantitatively assessing an amount of reperfusion that hasoccurred after opening an artery after a heart attack (i.e. usingangioplasty). Even after opening the cardiac artery one cannot determinethe extent that the heart muscle has died or quantify the severity of aheart attack (i.e. severe, moderate, light). Knowing this affectsprognosis and treatment for the patient. A further problem is decidingwhen to discontinue administration of thrombolysis, especially based ona quantitative determination. Another challenge is a quantitativelydetermining whether total occlusion of a coronary artery has occurred. Afurther challenge is quantitatively determining Whether a myocardialinfarction has occurred. One further major problem in cardiology,especially emergency cardiology, is differentiating between cardiacrelated chest pain, called ischemia, and non-cardiac related chest pain.It is especially challenging to make such a differentiationquantitatively. A further problem is unnecessary precautionaryhospitalizations of patients admitted to emergency rooms with chestpains after the patient is tested negatively for the presence of enzymesfrom necrosis and after ECG does not indicate a heart attack.

The invention, in some embodiments, differentially diagnoses whetherchest pain of a subject is cardiac related or is not cardiac related. Insome embodiments, the invention reaches a determination whether thechest is cardiac related (or whether the chest pain is suspected ofbeing cardiac related in other embodiments) and does so quantitatively,which is very useful for emergency cardiology. Moreover, in someembodiments, the determination that the chest pain is cardiac-related isvery strong due to the sensing, calculating, comparing and determiningsteps (and in the case of PEA without the calculating step) beingrepeated dynamically to show that the decline in MCI or PEA continueseven further (whereas in non-cardiac chest pain the MCI and PEA remainthe same or even increase). In some embodiments of the invention, aquantitative determination that chest pain is cardiac related or not ismade, and in some embodiments the quantitative determination is madewithout the need for an expert to interpret the results. In certainembodiments, this determination allows patients who are distant fromemergency rooms, or distant from doctors, to have such a determinationmade without consulting an expert.

The invention in some embodiments non-invasively quantities whether avictim of a heart attack sustained light, medium of severe damage from aheart attack. The invention, in some embodiments, quantitativelydetermines an amount of reperfusion that has occurred after opening theartery through angioplasty. The invention also quantitatively determinesan amount of restoration of function of the heart after opening theartery. For example, in some embodiments, the determined increase in MCIor PEA after the artery is opened is proportionate to the amount ofliving healthy heart muscle remaining in the patient. Accordingly,certain embodiments of the invention yield a measure of contractilereserve in the patient, which has great importance regarding the futureof the patient. Conversely, occluding a coronary artery, for exampleduring routine stent implantation, produces a decrease in PEA and MCIdue to ischemia. When the myocardium supplied by the artery beingoccluded is dead no change in PEA or MCI occurs. In some embodiments,the invention yields a measure of a decrease in MCI and PEA duringocclusion, which has great importance, since if there is viablemyocardium it can be saved and the function improved by a bypassoperation, etc.

It is important to assess, especially quantitatively, the effectivenessof thrombolysis, in which medication for dissolving the artery clot isadministered. This involves assessing whether the thrombolysis hassuccessfully dissolved the clot in the artery to a level of certaintythat allows doctor to comfortably discontinue the medication. Someembodiments of the invention allows one to determine, in someembodiments quantitatively, that thrombolysis has been effective, forexample by measuring an increase in the MCI or the PEA after thethrombolysis (relative to before the thrombolysis) and comparing themeasured increase to a predetermined amount of increase. The increase inPEA or MCI indicates reperfusion of blood in the artery and this isquantified in some embodiments. Knowing this is important since themedication used for thrombolysis has a side effect of hemorrhage, andalso because thrombolysis is not totally reliable at achieving success.Therefore, knowing when to discontinue the medication creates animportant medical benefit.

The invention, in certain embodiments, is capable of detecting a totalocclusion of a coronary artery in a mammalian subject, for example ifthe MCI or the PEA of the subject declined by at least a predeterminedamount relative to a baseline MCI or PEA. The invention, in someembodiments, utilizes MCI, or myocardial contractility index, whichcomprises a ratio between PEA (peak endocardial acceleration) and IVCT,the duration of the isovolumetric contraction portion of a systole phaseof a cardiac cycle of a subject, wherein in some embodiments the ratiois PEA/IVCT. By utilizing an index such as MCI as the measuredparameter, which index is proportional to two different parameters (PEAand the inverse of IVCT) that are each affected by occlusion, (PEAdecreased and IVCT is increased such that an inverse of IVCT isdecreased) the invention in some embodiments utilizes a parameter ismore sensitive to changes brought about by occlusion of an artery of theheart. Certain embodiments of the invention are usable at home and areusable for example without any professional interpretations. Forexample, in the emergency room, the PEA of the patient would havealready declined to its lowest point in many cases since patients oftenreach the emergency room only several hours after the initial insult,i.e. several hours after chest pain started. Therefore, no dynamicmeasurement of PEA or calculation of MCI is possible in these cases(these parameters are in any event not measured or calculated today todiagnose the case of the chest pain). However, at home, dynamicmeasurement of MCI and PEA is possible and useful in some embodiments ofthe invention. The invention reaches the determinations described hereinnon-invasively, and in some embodiments, without interpretations by anexpert.

The principles and operation of a system/apparatus and method forDetermining an Amount of Reperfusion in Myocardium and asystem/apparatus and method for Assessing Effectiveness of Thrombolysis,according to the invention may be better understood with reference tothe drawings and the accompanying description.

In the methods and apparatuses of the invention where there is abaseline MCI of the subject or an appropriate population of subjects,when comparing the MCI of the subject to the baseline MCI (acircumstance that is generally not applicable to embodiments herein thatmeasure reperfusion or that assess the effectiveness of thrombolysissince in both those cases there is no precise baseline other than thefirst MCI or the first PEA as a reference compared to the second MCI orsecond PEA), the baseline MCI is defined as one of (i) the baseline MCIof the subject, and (ii) a representative value of the baseline MCI of apopulation of subjects less a predetermined value. The predeterminedvalue is, in some embodiments, a predetermined number of standarddeviations, for example two standard deviations (2SD), from therepresentative value of the baseline MCI of the population of subjects.The representative value (for example a mean, median, average or otherrepresentative value) is for example a normal value, for example a meannormal value, of the baseline MCI of the population of subjects.Similarly, when comparing the PEA of the subject to a baseline PEA (acircumstance that is generally not applicable to embodiments herein thatmeasure reperfusion or that assess the effectiveness of thrombolysissince in both those cases there is no precise baseline other than thefirst PEA or first MCI as a reference to compare to the second PEA orsecond MCI), the baseline PEA is defined as one of (i) the baseline PEAof the subject, and (ii) a representative value of the baseline PEA of apopulation of subjects less a predetermined value. The predeterminedvalue is for example a predetermined number of standard deviations, forexample two standard deviations (2SD), from the representative value(for example a mean, median, average or other representative value)which for example is normal value, i.e. a mean normal value, of thebaseline PEA of the population of subjects. In one example, thepredetermined value is two standard deviations from a mean normal valueof a baseline PEA of the population of subjects. In this example, if thevalues of the PEA of a population of 70 subjects has a normaldistribution whose representative value (for example a mean, median,average or other representative value) is 20,000 in units ofacceleration such as dP/dtmax (or an equivalent number in units of G ormilig), and if the predetermined value is two standard deviations, thenif the standard deviation is plus or minus 3,000, the number 6,000 isthe predetermined value and the number 14,000 represents therepresentative value of the baseline PEA of the population of subjectsless the predetermined value. Note that since a decline and not anincrease in MCI or PEA is being measured, the representative value minusthe 2SD (not plus the 2SD) is utilized.

The reason that two standard deviations, or some other predeterminedvalue, is subtracted from the representative value to formulate the“baseline MCI” or to formulate the “baseline PEA”, when comparisons aremade (in any method or apparatus or system of the invention) to apopulation of subjects, instead of simply using the representative valueitself, is simply in order to be cautious in reaching the determinationinvolved (for example a determination that the chest pain is cardiacrelated). Accordingly, other examples of suitable predetermined valuessubtracted from the representative value of the baseline MCI (orbaseline PEA) are also appropriate in certain embodiments other than twoSD, such as one SD or zero SD or another number of SDs (or a differentsuitable predetermined value). For example if one is interested forwhatever reason in enduring greater risk and using less caution, in oneexample the predetermined value utilized is zero and the representativevalue of the baseline MCI (or PEA) of the population of subjects lessthe predetermined value is simply the representative value.

Applicant has conducted an experiment to measure the ability of MCI,wherein MCI=PEA divided by IVCT, to quantitatively detect ischemicepisodes and achieve other cardiac diagnostics (including not limited toamount of reperfusion, amount of viable myocardium and effectiveness ofthrombolysis). 60 to 70 human patients had arteriosclerosis and neededstent implantation. Before the stent implantation, a balloon was placedin the coronary artery as part of the routine. IVCT and PEA weremeasured simultaneously using an apparatus of the invention adapted tobe attached to the chest of the patient.

Statistical Summary of Data from Applicant's Study

A statistical analysis performed on preliminary data from a studyconducted by Applicant is presented. The objective of the study was toassess whether, by analyzing the change from baseline in MCI or PEA,ischemic episodes induced by balloon inflation can be detected. Subjectswho are scheduled to undergo diagnostic catheterization, after analyzingthe angiography the cardiologist in charge will decide if a stent shouldbe implanted in a proximal or mid arterial place. If this is the casethe patient is eligible for the trial. The patient signs an informedconsent for study participation before the beginning of thecatheterization. The elastic belt is placed on the patient withoutclosing it on the chest. After the cardiologist places the stent andprior to inflating the balloon the elastic belt is closed on the chestof the patient and continuous recording of the signals is performedduring balloon inflation for 25 sec, and during deflation, for a totalof 2 minutes. The elastic belt is then removed and the study iscompleted. The study endpoints include peak acceleration value (PEA) andMCI Index—calculated by the device's mathematical algorithm.

The required significance level of findings will be equal to or lowerthan 5%. All statistical tests will be two-sided. Where confidencelimits are appropriate, the confidence level will be 95%. Allstatistical analyses are performed using SAS v9.3 (SAS®, SAS InstituteCary, N.C. USA) software. PEA, MCI and the % change from baseline PEAand MCI values will be summarized by a mean, standard deviation,minimum, median and maximum. PEA and MCI values are compared between thethree different time points, with a paired t-test. The % change frombaseline in PEA is tested to see if it is lower than −10%, with at-test. The % change from baseline in MCI is tested to see if it islower than −20%, with a t-test. As a preliminary indication of whetherPEA and MCI can discriminate between Ischemia and No-Ischemia and ROCanalysis is performed using the log-transformed values of both. PEA andMCI, logistic regression is also performed to calculate the odds ratiosof detection of Ischemia with each of the variables. Finally a samplesize is calculated to test the hypothesis that PEA % reduction isgreater than 20%, and MCI greater than 30%.

A total number of 27 subjects were enrolled in the study and has dataavailable for the interim analysis. FIG. 14 shows an EXCEL file summaryof the results of the 27 subjects enrolled in the study. The total studywas 60-70 subjects.

Table 1 shows the distribution of PEA before, during and after Ischemia,and Table 2 shows the statistical comparison of the time points pairs ofPEA. We find that in ischemia PEA is statistically significantly(p<0.0001) lower than before ischemia. Once the balloon is deflated thePEA levels return to their baseline values, since the difference beforeto after is not significantly different from zero (p=0.3002)

Table 3 shows the distribution of the percent decrease in PEA frombaseline during ischemia, where we see that all patients had a decreasein PEA with the percentage ranging between 2.5% up to a 55% decrease.The mean reduction of 23.99% (SD=14.08%) was found statisticallysignificantly greater than 10% (p<0.0001, Table 4). The odds ratio fordetection of ischemia with PEA is 0.178 (p=0.0078), this means that forevery unit decrease in log-PEA the risk of ischemia is 5.6 times(1/0.178) higher (Table 5). FIG. 1 show the diagnostic accuracy in termsof the ROC curve and its summary measure the AUC (area under the curve)which equals 0.68 (low-moderate discriminatory power), this indicates apotential for discrimination.

TABLE 1 Distribution of PEA before, during and after Ischemia PEA BeforePEA In PEA After Ischemia Ischemia Ischemia N 27 27 27 Mean 22740 1688422198 SD 9343.4 6857.4 9709.6 Min 11052 7104.0 9969.0 Median 20323 1522220487 Max 42305 33837 44779

TABLE 2 Comparison of PEA before to during and before to after Ischemia,mean difference with 95% confidence interval and p-value of pairedt-test. Mean 95% CL Mean P-value Before-During 5855.0 3814.9 7895.2<0.0001 Before-After 542.0 −511.9 1595.8 0.3002

TABLE 3 Distribution of PEA % change from baseline to Ischemia % ChangePEA N 27 Mean −23.99% SD 14.08% Min −55.03% Median −19.47% Max −2.49%

TABLE 4 t-test of PEA % change from baseline to Ischemia, mean with 95%confidence interval. Mean 95% CL Mean P-value −23.99% −29.56% −18.42%<0.0001

TABLE 5 Odds ratio for the effect of PEA (log-transformed) indifferentiating between ischemia and no-ischemia with level ofsignificance 95% confidence interval 95% Wald Odds Ratio ConfidenceLimits P-value 0.178 0.050 0.634 0.0078

Table 6 shows the distribution of MCI before during and after Ischemia,and Table 7 the statistical comparison of the time points pairs of MCI.We find that in ischemia MCI is statistically significantly (p<0.0001)lower than before ischemia. Once the balloon is deflated the PEA levelsreturn to their baseline values, since the difference before to after isnot significantly different from zero (p=0.7014)

Table 8 shows the distribution of the percent decrease in MCI frombaseline during ischemia, where we see that all patients had a decreasein PEA with the percentage ranging between 3.75% up to a 73% decrease.The mean reduction of 32.39% (SD=16.6%) was found statisticallysignificantly greater than 20% (p=0.0006, Table 9). The odds ratio fordetection of ischemia with MCI is 0.225 (p=0.0031), this means that forevery unit decrease in log-MCI the risk of ischemia is 4.4 times(1/0.225) higher (Table 9). FIG. 2 shows the diagnostic accuracy interms of the ROC curve and its summary measure the AUC which equals 0.71(low-moderate discriminatory power), this indicates a potential fordiscrimination.

TABLE 6 Distribution of MCI before, during and after Ischemia MCI BeforeMCI In MCI After Ischemia Ischemia Ischemia N 27 27 27 Mean 838.96545.78 825.96 SD 436.65 275.71 456.24 Min 243.00 196.00 205.00 Median751.00 500.00 651.00 Max 1972.0 1291.0 2195.0

TABLE 7 Comparison of MCI before to during and before to after Ischemia,mean difference with 95% confidence interval and p-value of pairedt-test. Mean 95% CL Mean P-value Before-During 293.2 192.6 393.8 <0.0001Before-After 13.00 −55.91 81.91 0.7014

TABLE 8 Distribution of MCI % change from baseline to Ischemia % ChangeMCI N 27 Mean −32.39% SD 16.60% Min −73.83% Median −32.42% Max −3.75%

TABLE 9 t-test of MCI % change from baseline to Ischemia, mean with 95%confidence interval. Mean 95% CL Mean P-value −32.39% −38.96% −25.82%0.0006

TABLE 10 Odds ratio for the effect of MCI (log-transformed) indifferentiating between ischemia and no-ischemia with level ofsignificance 95% confidence interval 95% Wald Odds Ratio ConfidenceLimits P-value 0.225 0.084 0.606 0.0031

In conclusion, both PEA and MCI are significantly lower during ischemiathan before ischemia is induced. Mean % reduction in PEA 24%(SD=14.08%). Mean % reduction in MCI 32.4% (SD=16.6%). PEA mean %decrease has been found to be statistically significantly greater than10%. MCI mean % decrease has been found to be statisticallysignificantly greater than 20%. Statistically significant odds ratiosfor the detection of ischemia were found for both PEA and MCI with lowervalues indicating a higher risk of ischemia. AUC's were approximately0.7 for both. It is concluded that PEA and MCI show potential asdiagnostic measures for the detection of ischemia and for diagnosticactivities relating thereto.

As seen from FIG. 4, one embodiment of the invention is a method 100 ofnon-invasively differentiating diagnostically between chest pain that iscardiac related and chest pain that is not cardiac related, in amammalian subject that has a heart, the heart including ventricles.Method 100, in one embodiment, has a step 110 of non-invasively sensing,for example by a device positioned outside the subject, mechanicalvibrations that are from a mechanical contraction of for example atleast one of the ventricles of the heart of the mammalian subject, so asto simultaneously measure (a) IVCT, wherein in certain embodiments IVCTis a time duration of an isovolumetric contraction portion of a systolephase of a cardiac cycle of the subject; and (b) a peak endocardialacceleration (PEA) of the heart of the subject for example during theIVCT. In any embodiment, a device positioned outside the subjectincludes devices positioned adjacent the chest or other part of the bodyof the subject.

Method 100, in certain embodiments, has a further step 120 ofcalculating, for example dynamically and for example by one or moreprocessors programmed by suitable software, such as special purposesoftware stored on memory of a computer system, a myocardialcontractility index (MCI) of the subject such that the MCI comprises aratio of the PEA of the subject to the IVCT of the subject. In someembodiments the ratio is MCI=k·PEA/IVCT, where k is a constant. Incertain embodiments, k=1, such that the ratio is MCI=PEA/IVCT. The stepof calculating MCI in some embodiments is done dynamically such that asthe mechanical vibrations that are from a mechanical contraction of atleast one of the ventricles are sensed and measured, and as theamplitudes of the waveforms for the PEA are being measured the one ormore processors are dynamically calculating the MCI. In otherembodiments, the MCI is calculated at select junctures of method 100after the corresponding PEA is measured.

Method 100, in certain embodiments, has a further step 130 of comparingthe MCI of the subject to a baseline MCI, wherein the baseline MCI isone of (i) the baseline MCI of the subject, and (ii) a representativevalue of the baseline MCI of a population of subjects less apredetermined value. In one example, the predetermined value is apredetermined number of standard deviations from a mean normal value ofthe baseline MCI of the population of subjects, which for example is apopulation of subjects other than the subject. For example, for apatient/subject that is being treated in an emergency room for chestpain, one typically would not have a baseline for that subject. In thatcase, one uses, in some embodiments, a baseline of a population ofsubjects. Assume, in one non-limiting example, that a population ofsubjects has a range of values exhibiting a normal distribution whoserepresentative value (for example a mean, median, average or otherrepresentative value) is 20,000 g and whose representative value has astandard deviation of 3,000 g. Assume further in that example that twostandard deviations is the predetermined value. In this example, then,one takes the mean normal value (which is the representative value) ofthe baseline MCI of the population of subjects, which is 20,000 g, andsubtracts 6,000 g (the predetermined value) to yield 14,000 g as thebaseline MCI. The comparing step 130 is performed by the one or moreprocessors which are configured or programmed by software, for examplespecial purpose software that in some embodiments is stored on memory.

Method 100, in certain embodiments, has a further step 140 ofdetermining, for example by the one or more processors programmed bysoftware stored on memory, for example special purpose software, whetherthe MCI of the subject declined by at least a predetermined amountrelative to the baseline MCI, and if the MCI of the subject did declineby at least the predetermined amount, either (i) determining that thechest pains are cardiac related or (ii) determining that the chest painsare suspected of being cardiac related. In certain embodiments, thepredetermined amount is between one tenth and three-tenth, for exampleone-fifth and step 140, or a step subsequent to step 140, is determiningwhether the MCI of the subject declined by at least one-fifth relativeto the baseline MCI. In the illustrative example above, that would be20% less than 14,000 or 11,200 g. In some embodiments the predeterminedamount of MCI decline for determining that there is a suspicion that thechest pain is cardiac related is at least a certain fraction of thebaseline MCI, wherein that certain fraction is 10% or 15% or 16% or 17%or 18% or 19% or 20% or 21% or 22% or 23% or 24% or 25% or 26% or 30% orany range of percentages whose lower and upper limits are any of thesenumbers. These numbers are only examples and other numbers or fractionsor absolute amounts may apply instead.

The significance of the quantitative decline in MCI in this method 100and likewise the significance of quantitative declines in MCI and/or inPEA in other methods and apparatuses of the invention (described below)as indicators of the fact (or in other cases of the suspicion) thatchest pain is cardiac related is that Applicant's experiments show thatthe quantitative decline in MCI or PEA occurs due to the occlusion andcontinues as long as the occlusion continues, whereas it is known thatin non-cardiac chest pain the MCI and PEA remain the same or evenincreases.

In some embodiments there is a further step of outputting an alert thatthe chest pain is suspected of being cardiac related, i.e. ischemia. Forexample, if the MCI of the subject declined by one-fifth of the baselineMCI or by more than that, in the above case a reading of 11,200 g orless, in some embodiments, there would be a further step of outputtingan alert that there is a suspicion that the chest pain is cardiacrelated.

In some embodiments method 100 includes a step, for example a step thatis part of that is subsequent to step 140, comprised of outputting analert indicated that the chest pain is cardiac related. In certainembodiments this is based on a greater decline than would be needed todetermine a mere suspicion, since for example this to determine that thechest pain is cardiac related (or is definitely cardiac related). Forexample, in certain embodiments, step 140 is determining whether the MCIof the subject declined by at least a predetermined of betweenthree-tenths and one half, for example two-fifths, relative to thebaseline MCI such that it is determined that the subject's chest pain iscardiac related, or is definitely cardiac related. In some embodimentsthe predetermined amount of MCI decline for determining that the chestpain is or is definitely cardiac related, is at least a certain fractionof the baseline MCI, wherein that certain fraction is 30% or 35% or 37%or 38% or 39% or 40% or 41% or 44% or 45% or 50% or any range ofpercentages whose lower and upper limits are any of these numbers. Thesenumbers are only examples and other numbers or fractions or absoluteamounts may apply instead.

In the present patent application, when “a predetermined amount” isreferred to, both a relative amount qualifies as the “predeterminedamount” and an absolute amount qualifies as the “predetermined amount”.An example of a relative amount is a fraction or a percentage.

As seen from FIG. 5, one embodiment of the invention is a method 200 ofnon-invasively differentiating diagnostically between chest pain that iscardiac related and chest pain that is not cardiac related, in amammalian subject that has a heart, the heart including ventricles. Thismethod 200 generally tracks method 100 except that when the PEA ismeasured the MCI is not calculated from the PEA. Accordingly, thepredetermined amount is smaller in some embodiments of method 200compared to the predetermined amount utilized in method 100 since MCI ismore sensitive than PEA to blockages or occlusions of blood flow.

Method 200, in one embodiment, has a step 210 of non-invasively sensing,for example by a device positioned outside the subject, mechanicalvibrations that are from a mechanical contraction of for example atleast one of the ventricles of the heart of the mammalian subject, so asto measure a peak endocardial acceleration (PEA) of the heart of thesubject for example during an IVCT, wherein IVCT is in some embodimentsa time duration of an isovolumetric contraction portion of a systolephase of a cardiac cycle of the subject.

Method 200 has, in certain embodiments, a step 220 of comparing the PEAof the subject to a baseline PEA, wherein the baseline PEA is (i) thebaseline PEA of the subject or (ii) a representative value of thebaseline PEA of a population of subjects less a predetermined value. Insome embodiments the population of subjects is a population of subjectsother than the subject. The manner of selecting a representative valueand a predetermined value in method 200 is similar to that of method100. The comparing step 130 is performed by the one or more processorsprogrammed by software, for example special purpose software stored onmemory, in some embodiments. In certain embodiments, the one or moreprocessors obtain the PEA from digital signals that have been convertedfrom analog signals corresponding to the sensed mechanical vibrations.

Method 200 has, in some embodiments, a step 230 of determining by aprocessor programmed by software stored on memory, whether the PEA ofthe subject declined by at least a predetermined amount relative to thebaseline PEA, and if the PEA of the subject did decline by at least thepredetermined amount, either (i) determining that the subject's chestpains are cardiac related or (ii) determining that the chest pains aresuspected of being cardiac related. As in method 100, both a relativeamount qualifies to be the “predetermined amount” and an absolute amountqualifies to be the “predetermined amount”. An example of a relativeamount is a fraction or a percentage.

In some embodiments, step 230 comprises determining whether the PEA ofthe subject declined by at least a predetermined amount, thepredetermined amount being between one twentieth and one fifth, forexample at least one tenth relative to the baseline PEA. Method 200 hasa step, in some embodiments, of outputting an alert that there is asuspicion that the chest pain is cardiac related upon determining thatthe PEA of the subject declined by the predetermined amount, for examplewhen the predetermined is one tenth or another number between onetwentieth and one-fifth. In some embodiments the predetermined amount ofPEA decline for determining that there is a suspicion that the chestpain is cardiac related is at least a certain fraction of the baselineMCI, wherein that certain fraction is 5% or 9% or 10% or 11% or 12% or13% or 14% or 15% or 16% or 17% or 18% or 20% or any range ofpercentages whose lower and upper limits are any of these numbers. Thesenumbers are only examples and other numbers or fractions or absoluteamounts may apply instead.

In some embodiments, method 200 has a step of determining, by one ormore processors programmed by software stored on memory, whether the PEAof the subject declined by at least two tenths relative to the baselinePEA, which determination would indicate that the chest pain is ordefinitely is cardiac related. In some embodiments the predeterminedamount of PEA decline for determining that the chest pain is, ordefinitely is, cardiac related is at least a certain fraction of thebaseline MCI, wherein that certain fraction is between one tenths andthree-tenths, or for example 15% or 16% or 17% or 18% or 19% or 20% or21% or 21% or 22% or 23% or 24% or 25% or any range of percentages whoselower and upper limits are any of these numbers. These numbers are onlyexamples and other numbers or fractions or absolute amounts may applyinstead.

In some embodiments, there is a further step in method 200 of outputtingan alert that the chest pain is cardiac related.

In certain embodiments, the predetermined amount is a relatively highamount. For example, if the determination being made is not just thatthe chest pain is cardiac related but rather that the patient suffersfrom a myocardial infarction, the predetermined amount is, in certainembodiments, approximately twice as high as for determining definitecardiac related chest pains. For example, method 200 has, in certainembodiments, a step of determining myocardial infarction, for examplefrom detecting a lack of movement of ischemic and necrotic regions of aheart, as a result of detecting a decline in MCI of at least certainfraction relative to the baseline MCI, wherein the certain fraction isbetween half and four-fifths, for example four-fifths.

As shown in FIG. 12, in a further embodiment, particularly useful for apatient at home or distant from medical personnel, the invention is amethod 1100 of dynamically differentiating diagnostically,non-invasively, between chest pain that is cardiac related and chestpain that is not cardiac related, in a mammalian subject that has aheart, the heart including ventricles. Method 1100 comprises a step 1110of non-invasively sensing, by a device positioned outside the subject,mechanical vibrations that are from a mechanical contraction of at leastone of the ventricles of the heart of the mammalian subject, so as tosimultaneously measure (a) a first IVCT, wherein IVCT is a time durationof an isovolumetric contraction portion of a systole phase of a cardiaccycle of the subject; and (b) a peak endocardial acceleration (PEA) ofthe heart of the subject during the first IVCT.

Method 1100 also comprises in some embodiments a step 1120 one or moreprocessors of calculating a first myocardial contractility index (MCI)of the subject such that MCI comprises a ratio of the PEA of the subjectto the IVCT of the subject. In some embodiments the ratio isMCI=k·PEA/IVCT, where k is a constant. In one such embodiment, k=1, suchthat the ratio is MCI=PEA/IVCT. The one or more processors, programmedby special purpose software stored on memory, in some embodiments,calculates the first MCI from digital signals that derive from analogsignals corresponding to the mechanical vibrations sensed during thesecond period. Suitable hardware and software are included, in certainembodiments, to transmit and/or convert to digital form the data fromthe mechanical vibrations to the one or more processors for processing.This is the case for any method of the invention.

Method 1100 also comprises in certain embodiments a further step 1130 ofa predetermined length of time later, for example five minutes later,ten minutes later, or a different number of minutes between 5 minutesand 10 minutes later, than the first IVCT, non-invasively sensing by adevice positioned outside the subject mechanical vibrations that arefrom a mechanical contraction of at least one of the ventricles of theheart of the mammalian subject, so as to simultaneously measure (a) asecond IVCT; and (b) a peak endocardial acceleration (PEA) of the heartof the subject during the second IVCT. The examples of 5 minutes and 10minutes are non-limiting examples. Other suitable examples of timeintervals are usable in some embodiments such as 1, 3, 11, 13, 15, 17,18, 20, 25 or 30 minutes or a different number of minutes, where thisdifferent number is between 1 and 30 minutes, or at least such a numberof minutes or another suitable time interval.

In a step 1140 in some embodiments of method 1100, the one or moreprocessors calculate a second MCI of the subject, for example from thesecond IVCT and from the PEA measured during the second IVCT. Method1100 includes a step in certain embodiments of comparing the second MCIto the first MCI and determining, by the one or more processors, whetherthe second MCI is lower than the first MCI, and if the second MCI islower than the first MCI determining that the chest pain is cardiacrelated. The operating assumption is that whereas the MCI (and PEA)remains the same or increases in the case of non-cardiac related chestpain, the MCI (or PEA) declines over time in the case of cardiac relatedchest pain (until a certain point at which the decline has concluded).In some cases, the determining is determining whether the second MCI islower than the first MCI by at least a predetermined amount. This amountis between zero and a relatively small amount in some embodiments.

In some embodiments of method 1100 further verification of the declineis obtained by an additional step of continuing the dynamic measurementsof MCI by, beginning a predetermined length of time later, for examplefive minutes later, ten minutes later, or a different number of minutesbetween 5 minutes and 10 minutes later, or a different number of minutesbetween one and thirty minutes later, than the second IVCT,non-invasively sensing by a device positioned outside the subjectmechanical vibrations that are from a mechanical contraction of at leastone of the ventricles of the heart of the mammalian subject, so as tosimultaneously measure (a) a third IVCT; and (b) a peak endocardialacceleration (PEA) of the heart of the subject during the third IVCT,the one or more processors then calculating a third MCI of the subjectfrom the third IVCT and from the PEA measured during the third IVCT,comparing the third MCI to the second MCI (or to the baseline MCI) anddetermining, by the one or more processors whether the third MCI islower than the second MCI and if the third MCI is lower than the secondMCI, determining at a higher degree of certainty, that the chest pain iscardiac related so as to verify an earlier determination that the chestpain is cardiac related (the earlier determination being based on theearlier comparison between the first MCI and the second MCI), or else inother embodiments simply determining that the chest pain is cardiacrelated, if for example one prefers to not rely on the earlier declinefrom the first MCI to the second MCI.

As shown in FIG. 13, the invention, in a further embodiment, is a method1200 of dynamically differentiating diagnostically, non-invasively,between chest pain that is cardiac related and chest pain that is notcardiac related, in a mammalian subject that has a heart, the heartincluding ventricles. Method 1200 has a step 1210 in some embodiments ofnon-invasively sensing by a device positioned outside the subjectmechanical vibrations that are from a mechanical contraction of at leastone of the ventricles of the heart of the mammalian subject, so as tomeasure a first peak endocardial acceleration (PEA) of the heart of thesubject during a first IVCT wherein IVCT is a time duration of anisovolumetric contraction portion of a systole phase of a cardiac cycleof the subject.

Method 1200 has a step 1220 in some embodiments of, beginning apredetermined length of time later, for example five minutes later, tenminutes later, or a different number of minutes between 5 minutes and 10minutes later, or between 1 and 30 minutes later, than the first IVCT,non-invasively sensing by a device positioned outside the subjectmechanical vibrations that are from a mechanical contraction of at leastone of the ventricles of the heart of the mammalian subject, so as tomeasure a second peak endocardial acceleration (PEA) of the heart of thesubject during a second IVCT.

Method 1200 has a step 1230 in some embodiments of comparing the secondPEA to the first PEA and determining by one or more processors whetherthe second PEA is lower than the first PEA, and if the second PEA islower than the first PEA determining that the chest pain is cardiacrelated. In some cases, the determining is determining whether thesecond PEA is lower than the first PEA by at least a predeterminedamount. This amount is between zero and a relatively small amount insome embodiments. An output unit outputs an alert of the determinationin some embodiments.

In some embodiments of method 1200 further verification of the declineis obtained by an additional step of continuing the dynamic measurementsof PEA by, during a third sensing period beginning a predeterminedlength of time later, for example five minutes later, ten minutes later,or a different number of minutes between 5 minutes and 10 minutes lateror between 1 and 30 minutes later, than the second sensing period (asmeasured in some embodiments by being later than an end of the secondsensing period) non-invasively sensing by a device positioned outsidethe subject mechanical vibrations that are from a mechanical contractionof at least one of the ventricles of the heart of the mammalian subjectso as to measure a third PEA of the heart of the subject during an IVCTof the subject and comparing the third PEA to the second PEA (or to thebaseline PEA) and determining whether the third PEA is lower than thesecond PEA, and if the third PEA is lower than the second PEA, furtherverifying that the chest pain is cardiac related, or in otherembodiments determining that the chest pain is cardiac related if forexample one prefers to not rely on the earlier decline from the firstMCI to the second MCI. An output unit outputs an alert of thedetermination in some embodiments.

Methods 1100 and 1200 for dynamically differentiating diagnostically,non-invasively, between chest pain that is cardiac related and chestpain that is not cardiac related provide very strong indications ofischemia (cardiac-related chest pain) since the decline (of MCI or PEA)is shown to continue to decline dynamically.

In one embodiment shown in FIG. 3A, the invention is an apparatus 300configured to non-invasively medically diagnose whether chest pain iscardiac related or not, i.e. to differentiate diagnostically betweenchest pain that is cardiac related and chest pain that is not cardiacrelated, in a mammalian subject that has a heart, the heart includingventricles. The apparatus 300 in some embodiments comprises a sensorunit 310, which in some embodiments comprises a measurement device suchas an accelerometer unit 310 configured to non-invasively sense, by thedevice for example positioned outside the subject, mechanical vibrationsthat are from a mechanical contraction of at least one of the ventriclesof the heart of the mammalian subject so as to simultaneously measure(a) IVCT, wherein IVCT is a time duration of an isovolumetriccontraction portion for example of a systole phase of a cardiac cycle ofthe subject, and (b) a peak endocardial acceleration (PEA) of the heartof the subject during the IVCT. The accelerometer unit 310 is adapted tobe attached to a patient such as at the patient's chest, for exampleusing a belt, in some embodiments.

The sensor unit 310 comprises in some embodiments an accelerometer, amicrophone, straps and ECG electrodes. The purpose of the ECG electrodesis to identify appearance of the R peak of the QRS complex, whichcorresponds roughly to the opening of the isovolumetric contraction,whose time duration is represented by IVCT. FIG. 3C shows a non-limitingexample of a sensor unit 310 usable for apparatus 300. FIG. 3D shows anon-limiting example of a sensor unit 410 usable for apparatus 400. FIG.17 is a graph of an analog signal obtain by a sensor unit (310, 410), inaccordance with one embodiment of the invention. FIG. 18 is a graphshowing three signals, the top being an ECG signal, the bottom being amicrophone signal and the middle signal being an analog signal obtainedby a sensor unit, in accordance with one embodiment of the invention.From the graph of FIG. 17 and from the signal in the middle of FIG. 18,one computes the PEA, for example using techniques known in the medicalliterature. From the PEA and the IVCT, one or more processors executesoftware to compute the MCI. In some embodiments MCI=k·PEA/IVCT, where kis a constant. In one such embodiment, k=1, such that MCI=PEA/IVCT. TheECG signal is used to determine the location of the IVCT from the graph.

Apparatus 300 includes, in some embodiments, hardware 320 and software330 configured to convert the sensed mechanical vibrations into digitalsignals corresponding to the PEA and IVCT and usable by digitalprocessors. Examples of such hardware and software include signalconditioning circuitry and analog to digital converters. Apparatus 300includes in general in some embodiments any suitable hardware andsoftware for transmitting data or a signal(s) corresponding to thesensed mechanical vibrations, and/or converting to digital form thisdata or signal(s) corresponding to the sensed mechanical vibrations, tothe one or more processors 340 for use, processing, etc. The hardware320 and software 330 in some embodiments (see FIG. 3) is separate fromthe sensor unit 310 and from the one or more processors 340. In otherembodiments the hardware 320 and/or software 330 is part of one or moreof the sensor unit 310 and the one or more processors 340.

Apparatus 300 also includes in some embodiments one or more processors340, programmed by special purpose software 340A that in someembodiments is stored on a memory 340B. The one or more processors 340are part of or comprise in some embodiments a determination unit 344.The determination unit 344 is a computer system in some embodiments. Theone or more processors or the determination unit is configured toreceive digital signals corresponding to the sensed mechanicalvibrations and to calculate, for example dynamically, an MCI of thesubject. MCI is a myocardial contractility index that comprises a ratioof the PEA of the subject to the IVCT of the subject. The one or moreprocessors 340 (or determination unit) are configured to receive thesignals from the sensor unit 310 either through a wired connection orwirelessly.

The one or more processors are in some embodiments configured bysoftware to compare the MCI of the subject to a baseline MCI, whereinthe baseline MCI is one of (i) the baseline MCI of the subject, and (ii)a representative value of the baseline MCI of a population of subjectsless a predetermined value, i.e. a predetermined number of standarddeviations from the representative value (the representative value beingfor example a mean, median, average or representative value), forexample the mean normal value, of the baseline MCI of a population ofsubjects. The manner of selecting the representative value and thepredetermined value for apparatus 300 (and for apparatus 400) is similarto that described in connection with methods 100, 200. The one or moreprocessors are in some embodiments configured by software to determinewhether the MCI of the subject declined during the sensing period by atleast a predetermined amount relative to the baseline MCI.

The at least the predetermined amount (relative to the baseline MCI) isat least one-fifth in some embodiments, for example when thedetermination is whether or not there is a suspicion that the chest painis cardiac related. In some embodiments, the at least a predeterminedamount is at least a certain fraction of the baseline MCI, wherein thatcertain fraction is 15% or 16% or 17% or 18% or 19% or 20% or 21% or 21%or 22% or 23% or 24% or 25% or any range of percentages whose lower andupper limits are any of these numbers. These numbers are only examplesand other numbers or fractions or absolute amounts may apply instead.

In some embodiments, an output unit outputs an alert that there is asuspicion that the chest pain is cardiac related when at least thepredetermined amount has been reached. In some embodiments, thepredetermined amount is a certain fraction wherein the certain fractionof the baseline MCI is two-fifths, for example when the determination iswhether or not the patient's chest pain is cardiac related or not, or isdefinitely cardiac related or not. Instead of two-fifths, thepredetermined amount in some embodiments is a fraction of the baselineMCI between three-tenths and one half, or 52%, 56%, or 60% or any rangeof percentages whose lower and upper limits are any of these numbers.These numbers are only examples and other numbers or fractions orabsolute amounts may apply instead.

Apparatus 300 in some embodiments includes an output unit 350 thatoutputs an alert that the chest pain is cardiac related when at leastthe predetermined amount of decline is reached. Output unit 350 and oneor more processors 340 are part of the same computer system in someembodiments and in other embodiments they are not part of a samecomputer system.

As shown in FIG. 3B, the invention, in one embodiment, is an apparatus400 (or system 400) configured to non-invasively medically diagnosewhether chest pain is cardiac related or not, i.e. to differentiatediagnostically between chest pain that is cardiac related and chest painthat is not cardiac related, in a mammalian subject that has a heart,the heart including ventricles. Apparatus 400 comprises in someembodiments a sensor unit 410, which in some embodiments comprises ameasurement device such as an accelerometer unit 410 configured tonon-invasively sense, by the device positioned outside the subject,mechanical vibrations that are from a mechanical contraction of at leastone of the ventricles of the heart of the mammalian subject so as tomeasure a peak endocardial acceleration (PEA) of the heart of thesubject during an IVCT, wherein IVCT is a time duration of anisovolumetric contraction portion of a systole phase of a cardiac cycleof the subject. The accelerometer unit 410 is adapted to be attached toa patient such as at the patient's chest, for example using a belt, insome embodiments.

Apparatus 400 includes, in some embodiments, hardware 420 and software430 configured to convert the sensed mechanical vibrations into digitalsignals corresponding to the PEA. An example of such hardware andsoftware is an analog to digital converter. Apparatus 400 includes, insome embodiments any suitable hardware and software for transmitting thesensed mechanical vibrations to one or more processors 440. Furthermore,any of the methods of the invention have, in some embodiments, suchsuitable hardware and software for transmitting, and/or converting todigital form, data or a signal(s) corresponding to the sensed mechanicalvibrations to the one or more processors 440 for use, processing,analysis, etc. The hardware 420 and software 430 in some embodiments(see FIG. 3) is separate from the sensor unit 410 and from the one ormore processors 440. In other embodiments the hardware 420 and/orsoftware 430 is part of one or more of the sensor unit 410 and the oneor more processors 440.

Apparatus 400 includes in some embodiments one or more processors 440programmed by special purpose software 440A that in some embodiments isstored on a memory 440B. The one or more digital processors are part ofa determination unit 444 in some embodiments. In some embodiment thedetermination unit 444 is a computer system. The one or more processorsor the determination unit is configured to receive digital signalscorresponding to the sensed mechanical vibrations, to compare thedigital signals that correspond to the PEA of the subject to a baselinePEA, wherein the baseline PEA is one of (i) the baseline PEA of thesubject and (ii) a representative value (for example a mean normalvalue) of the baseline PEA of a population of subjects less apredetermined value, i.e. a predetermined number of standard deviationsfrom the representative value (the representative value being forexample a mean, median, average or other representative value), and todetermine whether chest pain of the subject is cardiac related or notcardiac related based on whether the PEA of the subject declined duringthe sensing period by at least a predetermined amount relative to thebaseline PEA. The one or more processors 440 (or determination unit) areconfigured to receive the signals from the sensor unit 410 eitherthrough a wired connection or wirelessly.

The one or more processors 440 are configured by software 440A stored onmemory 440B in some embodiments to determine whether there is merely asuspicion that the chest pain is ischemia. Especially (although notnecessarily only) in such cases, the predetermined amount is one tenthsuch that if the decline is at least one tenth relative to the baselinePEA there is such a suspicion. Instead of one-tenth, the predeterminedamount, in some embodiments is a certain fraction of the baseline PEA,for example between one twentieth and one fifth, or wherein that certainfraction is 9% or 10% or 11% or 12% or 13% or 14% or 15% or 16% or 17%or 18% or any range of percentages whose lower and upper limits are anyof these numbers. These numbers are only examples and other numbers orfractions or absolute amounts may apply instead.

An output unit 450 in some embodiments outputs an alert. For example,output unit 450 outputs that there is a suspicion that the chest pain iscardiac related, i.e. ischemia, in some embodiments, when the selectedpredetermined amount is reached. The one or more processors 440 areconfigured by software in some embodiments to determine whether thechest pain is ischemia or is definitely ischemia. In such cases,although not necessarily only in such case, the predetermined amount istwo tenths such that if the decline is at least two tenths relative tothe baseline PEA, the chest pain is determined to be ischemia. Insteadof two-tenths, in some embodiments the predetermined amount relative tothe baseline PEA is a certain fraction of the baseline PEA, for examplebetween one tenth and three-tenths, or wherein that certain fraction is15% or 20% or 22% or 24% or 26% or 28% or any range of percentages whoselower and upper limits are any of these numbers. These numbers are onlyexamples and other numbers or fractions or absolute amounts may applyinstead.

An output unit 450 of apparatus 400 outputs an alert that the chest painis cardiac related, i.e. ischemia, in some embodiments when the selectedpredetermined amount relative to the baseline PEA (which may be acertain fraction such as two-tenths in this case) is reached. Outputunit 450 and one or more processors 440 are part of the same computersystem in some embodiments and in other embodiments they are not part ofa same computer system.

Output unit 350 of apparatus 300 and/or output unit 450 of apparatus 400comprises, in some embodiments, an indicator unit in communication withthe determination unit, the indicator unit configured to issue anindication of at least one of (i) whether the chest pain is cardiacrelated or not and (ii) whether the chest pain is suspected of beingcardiac related or not.

Notwithstanding FIGS. 3A and 3B, some embodiments of apparatus 300and/or apparatus 400 are defined so as to not include the analog todigital converter or other hardware and software configured to convertthe analog signal to a digital signal.

Any apparatus of the invention may be described as a “system” if the oneor more processors are remote from the measurement device and forexample the one or more processors are configured to communicate to themeasurement device and or associated hardware and software wirelesslyand/or the sensor unit or measurement device is configured tocommunicate to the one or more remote processors.

Apparatus 300 and apparatus 400 are in some embodiments configured toimplement the “dynamic” embodiments outlined in methods 1300 and 1400 aswell as any of the other methods or embodiments of the invention.

The following paragraphs numbered (a) through (k) contain a moredetailed description of one non-limiting example of how to implement anapparatus 300 or apparatus 400 and it is emphasized that the detailstherein are not intended to at all limit the range of possibleembodiments of apparatus 300, 400 or possible ways to implementapparatus 300, 400 or methods using apparatus 300, 400.

(A) In some embodiments, apparatus 300, 400 is a non-invasive cardiacmonitor configured to measure, process, store and/or display informationderived in certain embodiments from a sensor such as an accelerometer(configured in certain embodiments to record vibrational waveformsproduced by the heart contractions and transmitted to the chest wall)and in some embodiments also one or more of an electrocardiogram (ECG)and a microphone. Apparatus 300, 400, in some embodiments, is configuredto measure the timing of part of the events in the cardiac cycle.Apparatus 300, 400 in some embodiments where the user is for example athome provides a cardiac parameter which in some embodiments indicatesmyocardial ischemia (or a pattern of myocardial ischemia) for furtheranalysis by the physician, which is particularly useful for patientswith suspected cardiac abnormalities away from medical personnel. In aparticular embodiment, apparatus 300, 400 measures and monitors ECGsignals, mechanical action of the heart by an accelerometer and theaudio signals of the heart using a microphone in some embodiments. Inother embodiments of the invention, apparatus 300, 400 omits one or moreof (i) the ECG leads and (ii) the microphone. For example, in someembodiments apparatus 300, 400 senses and monitors signals from anaccelerometer and ECG signals but does not measure or monitor audiosignals of the heart from a microphone. In still other embodiments ofthe invention, apparatus 300, 400 does not measure and monitor ECGsignals and only senses and monitors (and analyzes) vibrationalwaveforms produced by the heart's mechanical contractions andtransmitted to the chest wall (with or without audio signals from amicrophone).

(B) In certain embodiments of apparatus 300, 400, the apparatuscomprises the following three main components: (i) a sensor unit 310,410 that includes an elastic belt fitted with for example twoaccelerometer sensors, ECG leads and a microphone; (ii) a hand-heldportable operation unit 325, 425, battery powered digitizing transceiverunit with an embedded micro-processor and (iii) dedicated software340A,440A configured to perform data analysis and hosted on a computersuch as a personal computer (PC) 340, 440 or laptop computer 340, 440 orany other appliance having within it a suitable processor and software,and also configured for control of other components.

(C) The elastic belt 311, 411 with the sensors 312, 412 is configured tobe attached for example to the chest of the patient for example with thesensors adjacent the chest of the subject according to some embodiments.The sensor unit 310, 410 provides mechanical vibration correlatedsignals, ECG signals and audio signals but in other embodiments providesadditional signals (i.e. from additional sensors) and in still otherembodiments provides fewer signals (i.e. from fewer sensors). Thededicated software hosted by the PC analyzes the recorded waveform andmeasures a timing of parts of the events in the cardiac cycle.

(D) FIGS. 3C-3D show the main components of apparatus 300, 400 in someembodiments. The operation unit 325, 425 in some embodiments includeshardware 320, 420 and software 330, 430 and in one embodiment isresponsible for digitizing the captured data and transmitting the datavia a secure USB connection reliably to the application software hostedon a PC. In this embodiment, the operation unit has a Microcontroller(which in this particular embodiment is identified as STM32L151VD CortexM3) which provides communication of the system with the host PC and thebelt. FIG. 3E shows a block diagram of apparatus 300, 400 with threecomponents.

(E) Sensors 311, 411 are attached to the chest in some embodiments andin some embodiments monitor cardiac function by sensing the electricalsignal (ECG signals), mechanical vibration correlated signals(contraction) forces and acoustic sound (Microphone) generated by theheart. Apparatus 300, 400 records the movement of the heart during eachcardiac cycle (heartbeat) in some embodiments. The heart movement issensed in certain embodiments by a tri-axial accelerometer (X, Y, Z)aligned to the heart. Electrocardiograph (ECG) signals are sensed andrecorded simultaneously with the accelerometers data. The data isanalyzed by the dedicated software and displayed on the computer.

(F) Apparatus 300, 400 in one embodiment uses modem digital technologyto capture, process, analyze and record the motion of the patient'ssternum resulting from the movement of the heart during each cardiaccycle (heart beat). The vibrations, or forces, are detected usinghigh-sensitivity, calibrated, tri-axial accelerometer-based technology.This movement of the heart is sensed by two three-axis accelerometers inthis embodiment and is processed digitally and displayed. Oneaccelerometer sensor is located in one embodiment on the sternum andsenses all the vibrations (“outside” and heart related). The secondaccelerometer is isolated from the sternum in this embodiment and sensesonly the “outside” vibrations. Software 340A, 440A uses an algorithmthat in certain embodiments combines and calculates the data from thetwo accelerometers and provides filtered data of the heart relatedvibrations. Sensor unit 310, 410 in certain embodiments represents thedata of the forces created by the heart and displayed with theacceleration amplitudes as the vertical axis and time as the horizontalaxis. The measurements are expressed as milli-gravity over time inmilliseconds. Data is displayed on a computer screen of a computer 340,440 and dedicated software 340A, 440A provides tools for furtheranalysis. The accelerometer data is sensed, recorded and displayedsynchronously with the ECG and the Microphone in this embodiment.

(G) Electrocardiograph data is a Trans-Thoracic Echocardiogram (TTE)interpretation of the electrical cavity of the heart over a period oftime, as detected by electrodes attached to the surface of the skin andrecorded by a device external to the body. An ECG is used to measure thepatient heart's electrical conduction system. It picks up electricalimpulses generated by the polarization and depolarization of cardiactissue and translates it into a waveform. Some embodiments of apparatus300, 400 include an ECG device with an embedded processor containing anECG data acquisition module, data memory storage, and data processingcapabilities. In one embodiment, apparatus 300, 400 reads three leads ata sample rate of 1000 Hz at the following points: LI, LII, LIII, aVL,aVR, aVF and V1-V6. In addition, apparatus 300 in some embodimentsautomatically filters ECG signal noise sources: filter automaticallyselected, RFI noise sources, wandering signals, patients' breathartifacts and patient's motion artifacts. The ECG data is sensed,recorded and displayed synchronously with the accelerometer and theMicrophone in certain embodiments.

(H) When the myocardium contracts isometrically it generates vibrationswhich have audible components that are responsible for the first heartsound. The audible spectrum of these vibrations is measured with amicrophone in some embodiments. In addition, apparatus 300 in someembodiments is configured to automatically filter Microphone signalnoise sources (acoustic sound): filter automatically selected, RFI noisesource, wandering signals, patients' breath artifacts and patient'smotion artifacts. FIG. 18 shows ECG signals, Accelerometer andMicrophone graphs.

(I) Dedicated software 340A, 440A also identifies the time of part ofthe events in the cardiac cycle in certain embodiments. Cardiac timeintervals are regulated by the mechanics and functions of the myocytes;therefore, these intervals are a good measure of the cardiac function.Dedicated software 340A, 440A analyzes the waveforms which are capturedfrom accelerometer and ECG sensors in one embodiment and shows thetiming of the following events in the cardiac cycle including: (a)Electromechanical delay (EMD) from R-peak to Mitral valve Closure (MC);(b) Pre-Ejection Time (PET)—from R-peak to aortic valve opening (AO);(c) Isovolumetric Contraction Time (IVCT)—from mitral valve closure toaortic valve opening. The first two points, measured in each cardiaccycle, are used to compute the IsoVolumetric Contraction Time(IVCT=PET−EMD). From the waveforms captured by the accelerometer the PEAis measured and from the PEA and the IVCT, one or more processorsexecute the dedicated software to compute the MCI. In some embodimentsMCI=k·PEA/IVCT, where k is a constant. In one such embodiment, k=1, suchthat MCI=PEA/IVCT.

(J) Apparatus 300, 400 in some embodiments also displays to a physicianthe timing of the three following events: Aortic Valve Closed (AVC),Mitral Valve Closed (MVC) and the IsoVolumetric Contraction Time (IVCT).In certain embodiments, apparatus 300, 400 provides accurate timing ofpart of the event of the cardiac cycle, at least as accurate as anechocardiogram. The vibration peak is known as the Peak EndocardialAcceleration (PEA). PEA is defined as the maximum peak-to-peak amplitudeduring a window 50 ms before to 200 ms following the peak R wave (ECG).The PEA occurs in the isovolumetric contraction phase.

(K) One particular non-limiting example of the use of the apparatus 300,400 is as follows. A patient wears the belt 311, 411 of the sensor unit310, 410 and attaches the sensors 312, 412 of the sensor unit 310, 410to his or her chest, as described in a user manual. When the patientwears the belt in the correct position, an indication is presented onthe LCD screen 325A, 425A of the operation unit 325, 425 and the datacapture can begin and the data recording starts. After the patient heartdata capture is complete, the operation unit 325, 425 is connected tothe PC 340, 440 equipped with the dedicated software, for example via aUSB cable. In other embodiments of apparatus 300, 400 some or all datatransmission is performed wirelessly. The controlling softwareapplication 340A, 440A in some embodiments has the features andfunctions needed to communicate with and control the sensor unit 310,410, operation unit 325, 425 and personal computer 340, 440 of apparatus300, 400. Once communication between the operation unit and thecomputer, i.e. PC, is established, the software 340A, 440A is configuredto stream continuous data from the operation unit 325, 425, record thedata streams, and manually analyze the recorded data. In addition, theoperation unit's battery status is displayed on the operation unit's LEDdisplay. A notification for replacing the battery is presented on theLED display.

The above apparatus 300, 400 is used to implement a wide variety ofmethods of the invention including any of those described herein.Notwithstanding this, in going from one PEA embodiment to another PEAembodiment, and in going from one MCI embodiment to another MCIembodiment, for example in going from one apparatus or method configuredto ascertain a quantitative amount of reperfusion in the myocardiumversus another apparatus or method configured to ascertain whether chestpain is or is not cardiac-related, there would be differences in thespecial purpose software 340A, 440A (and hence there would bedifferences in what is stored on the memory) and in the step taken bythe determination unit or software since the determinations differ. Inaddition, one would find differences in the output unit 350, 450 and thestep of outputting since the outputs and alerts as to what wasdetermined differ.

As shown in FIG. 6, the invention, in one embodiment, is a method 500 ofdetecting a total occlusion of a coronary artery in a mammalian subjectthat has a heart, the heart including ventricles. Method 500, in oneembodiment, comprises a step 510 of, for example by a device positionedoutside the subject, non-invasively sensing mechanical vibrations thatare from a mechanical contraction of at least one of the ventricles ofthe heart of the mammalian subject, so as to simultaneously in someembodiments measure (a) IVCT, wherein in some embodiments IVCT is a timeduration of an isovolumetric contraction portion of a systole phase of acardiac cycle of the subject; and (b) a peak endocardial acceleration(PEA) of the heart of the subject for example during the IVCT.

Method 500 also includes a step 520 in some embodiments of calculating,for example dynamically, a myocardial contractility index (MCI) of thesubject such that the MCI comprises a ratio of the PEA of the subject tothe IVCT of the subject. The MCI is calculated in some embodiments byone or more processors directly or indirectly from signals correspondingto the sensed mechanical vibrations. In some embodiments,MCI=k·PEA/IVCT, where k is a constant. In certain embodiments, k=1, suchthat MCI=PEA/IVCT. The step of calculating MCI in some embodiments isdone dynamically such that as the PEA is being measured, the one or moreprocessors is/are dynamically calculating the MCI. In other embodiments,the MCI is calculated only at select junctures of method 500.

Method 500 in some embodiments has a step 530 of comparing the MCI ofthe subject during the sensing period to a baseline MCI, wherein thebaseline MCI is one of (i) the baseline MCI of the subject, and (ii) arepresentative value of the baseline MCI of a population of subjectsless a predetermined value. The predetermined value is for example anumber of standard deviations, for example two, from the representativevalue (the representative value being for example a mean, median,average or other representative value), which in some cases is a “meannormal value” of the baseline MCI of a population of subjects, as thatterm has been previously explained.

Method 500 in some embodiments has a step 540 of determining that therehas been a total occlusion of the coronary artery in the subject if theMCI of the subject declined during the sensing period by at least apredetermined amount relative to the baseline MCI. In some case, method500 has a step of determining that there has been a total occlusion ofthe coronary artery in the subject if the MCI of the subject declinedduring the sensing period by at least one-fifth relative to the baselineMCI. Instead of one-fifth in some embodiments the predetermined amountrelative to the baseline MCI is a certain fraction of the baseline MCIof between one-tenth and three-tenths or 16% or 19% or 24% or 28% or 33%or 40% or 50% or 60% any number in between. These numbers are onlynon-limiting examples of predetermined amounts.

As shown in FIG. 7, in a further embodiment, the invention is a method600 of detecting a total occlusion of a coronary artery in a mammaliansubject that has a heart, the heart including ventricles. Method 600includes a step 610 in some embodiments of non-invasively sensingmechanical vibrations that are from a mechanical contraction of at leastone of the ventricles of the heart of the mammalian subject so as tomeasure a peak endocardial acceleration (PEA) of the heart of thesubject for example during an IVCT, wherein IVCT is a time duration ofan isovolumetric contraction portion of a systole phase of a cardiaccycle of the subject. Method 600 has a further step 620 in someembodiments of comparing the PEA of the subject during the sensingperiod to a baseline PEA, wherein the baseline PEA is (i) the baselinePEA of the subject or (ii) a representative value of the baseline PEA ofa population of subjects less a predetermined value. The predeterminedvalue is for example a predetermined number of standard deviations, forexample two standard deviations, from the representative value (therepresentative value being for example a mean, median, average or otherrepresentative value), which in some cases is a mean normal value, ofthe baseline PEA of a population of subjects. The population of subjectsis for example a population of subjects other than the subject beingdiagnosed.

Method 600 also has in some embodiments a further step 630 ofdetermining that there has been a total occlusion of the coronary arteryin the subject if the PEA of the subject declined during the sensingperiod by at least a predetermined amount relative to the baseline PEA.For example, method 600 has a step in some embodiments of determiningthat there has been a total occlusion of the coronary artery in thesubject if the PEA of the subject declined during the sensing period byat least one-tenth relative to the baseline PEA, or by a certainfraction of the baseline PEA between one twentieth and one fifth or 9%or 11% or 12% or 13% or 14% or 15% or 16% or 17% or 18% or anotherpercent (since these numbers are only non-limiting examples ofpredetermined amounts relative to the baseline PEA).

An extension of methods 500 and 600 is an embodiment of the invention inwhich beyond determining total occlusion, one also determines an acutemyocardial infarction. For example, if the determination being made isnot just total occlusion but also that the total occlusion persisted fora predetermined amount of time, for example at least 30 minutes, or atleast 40 minutes or at least 50 minutes or at least 60 minutes (oranother amount of time between 25 and 65 minutes) then it is determinedthat the patient suffered an acute myocardial infarction caused by thetotal occlusion. For example, method 500 and method 600 each have, incertain embodiments, a further step of repeating, or dynamicallyrepeating, the sensing, calculating, comparing, determining of MCI orthe sensing, comparing, determining of the PEA, so as to determine acutemyocardial infarction from a determination that the decline in MCI orPEA sufficient to trigger the determination of total occlusion persistedfor at least the predetermined amount of time, such as 30 minutes orsome other specified amount of time falling between a range of 30 to 60minutes. This further step, in some embodiments comprises repeating thesensing, calculating, comparing and determining steps (i.e. steps 510,520, 530 and 540) for method 500 or repeating the sensing, comparing anddetermining steps (i.e. steps 610, 620 and 630) for method 600, forexample 25 or 30 minutes later or 40 minutes later or 50 minutes lateror 60 or 65 minutes later (or another amount of time later between 25and 65 minutes later) so as to determine that at least a predeterminedamount of time has passed since the total occlusion (i.e. the totalocclusion has persisted for at least that predetermined amount of time)and that therefore an acute myocardial infarction has occurred, whereinthe predetermined amount of time falls within 25 to 65 minutes (forexample at least 30 minutes or at least 60 minutes).

A still further embodiment of the invention shown in FIG. 8 is a method700 of determining an amount of viable (or salvageable) myocardiumsupplied by an artery of a mammalian subject after a heart attack of themammalian subject. Method 700 comprises a step 710 in some embodimentsof during a first sensing period after a heart attack but before openingthe artery, i.e. angioplasty, non-invasively sensing, for example by adevice positioned outside the subject, mechanical vibrations that arefrom a mechanical contraction of at least one of the ventricles of theheart of the mammalian subject, so as to simultaneously measure (a)IVCT, wherein IVCT is for example a time duration of an isovolumetriccontraction portion of a systole phase of a cardiac cycle of thesubject; and (b) a peak endocardial acceleration (PEA) of the heart ofthe subject during the IVCT.

Method 700 has in some embodiments a step 720 of calculating a firstmyocardial contractility index (MCI) of the subject such that MCIcomprises a ratio of the PEA of the subject to the IVCT of the subject.In some embodiments this ratio is MCI=k·PEA/IVCT, where k is a constant.In one such embodiment, k=1 such that the ratio is MCI=PEA/IVCT.

The step of calculating the MCI in some embodiments is done dynamicallysuch that as the PEA is being measured one or more processors aredynamically calculating the MCI. In other embodiments, the MCI iscalculated only at select junctures of method 500. The step ofcalculating is done from digital signals derived from analog signalsthat correspond to the sensed mechanical vibrations.

Method 700 has in some embodiments a step 730 of, during a secondsensing period, after a heart attack but before opening the arterynon-invasively sensing, for example by a device positioned outside thesubject, mechanical vibrations that are from a mechanical contraction ofat least one of the ventricles of the heart of the mammalian subject, soas to simultaneously measure (a) IVCT, wherein IVCT is a time durationof an isovolumetric contraction portion of a systole phase of a cardiaccycle of the subject; and (b) a peak endocardial acceleration (PEA) ofthe heart of the subject during the IVCT.

Method 700 has in some embodiments a step 740 of calculating a secondMCI of the subject, for example directly or indirectly from signalscorresponding to the mechanical vibrations sensed during the secondperiod.

Method 700 in some embodiments has a step 750 of determining, forexample by a processor, an amount by which the second MCI exceeds thefirst MCI, said amount being proportionate to a viable myocardiumsupplied by the artery.

A further embodiment of the invention is a non-invasive apparatus 400configured to non-invasively determine an amount of reperfusion of bloodto a myocardium supplied by an artery of a mammalian subject after aheart attack of the mammalian subject. The apparatus 400 may comprise asensor unit 410 configured to non-invasively sense from outside thesubject mechanical vibrations that are from a mechanical contraction ofat least one of the ventricles of the heart of the mammalian subject soas to simultaneously measure (a) IVCT, wherein IVCT is a time durationof an isovolumetric contraction portion of a systole phase of a cardiaccycle of the subject; and (b) a peak endocardial acceleration (PEA) ofthe heart of the subject during the IVCT. The apparatus 400 may alsoinclude a determination unit 444 comprising one or more processors 440programmed by software stored on a memory. The determination unit 444may be configured to receive digital signals corresponding to the sensedmechanical vibrations, and to determine the PEA during the IVCT. Thedetermination unit 444 may include a perfusion module for determining,by one or more processors 440, that execute program code 440A (forexample software 440A) stored on memory 440B, an amount of reperfusionin the myocardium. The perfusion module in one embodiment is part of theprogram code 440A executed by the one or more processors 440 of thedetermination unit 444. The determination unit 444 may accomplish thisby the one or more processors 440 comparing a first PEA of the subjectsensed by the sensor unit 410 after a heart attack but before openingthe artery to a second PEA of the subject sensed by the sensor unit 410at a subsequent time after opening the artery. The amount of reperfusionis expected to be proportionate to how much viable myocardium (suppliedby the artery) remains in the subject. The determination unit 444 may beconfigured to determine a degree of restoration of function of thesubject's heart derived from the opening of the artery.

For example, one typically would not have a baseline reference for PEA(or a baseline MCI, which is calculated from PEA) for a patient who hassuffered a heart attack. Accordingly, in one embodiment, the effectivebaseline that is used is the PEA level of the subject taken after theheart attack but before the opening of the artery (for example usingangioplasty) which is referred to herein as “first PEA”. In onenon-limiting example, the first PEA taken is equal to 6,000 in units ofacceleration units (for example dP/dtmax or an equivalent number inunits of G or milig) for a particular subject. The second PEA takenlater after the artery has been opened, for example using angioplasty,is equal to 7,200 in the same units of acceleration. According to this,in this case one concludes that there has been 20% reperfusion. In someembodiments, one assumes that the population of subjects that thissubject fits into would normally have a PEA equal to 20,000 in the sameunits of acceleration. Under this assumption, reperfusion has been onlypartial. But the determination of the amount of reperfusion in themyocardium of the subject is very useful information for a number ofreasons. It helps determine the severity of the heart attack (forexample, mild, moderate, severe). It helps determine the degree(especially a quantitative degree) of restoration of function of thesubject's heart derived from the procedure, i.e. angioplasty. It alsomay yield a measure, i.e. a quantitative measure, of contractile reservein the patient, which has great importance regarding the future of thepatient.

Since the pre-myocardial infarction PEA is typically unknown, one alwaysassumes a partial restoration of function since one never knows theexact pre-MI PEA. However, if the second PEA is close enough to thenormal values based on the population of subjects that the subject fitsinto, one assumes that it is a complete or near complete reperfusion anda near or complete restoration of function. In contrast, if the secondPEA stayed well below normal values (as defined by the population ofsubjects that the subject fits into) one concludes that the reperfusionwas a partial reperfusion and the restoration of function was a partialrestoration of function.

The output unit 450, in one embodiment, may output a percentage or otherquantitative measure of reperfusion, or in other embodiments a range ora category (by way of non-limiting example, “partial”, “moderate”, “nearcomplete”, “complete”) of reperfusion in the myocardium. In anotherembodiment, output unit 450 outputs raw data of the first PEA and secondPEA. In still another embodiment, output unit 450 outputs a quantitativeamount, a range a degree or a category (i.e. partial, moderate, nearcomplete, complete) of restoration of function. In another embodiment,the output unit 450 outputs an amount, a percentage, or otherquantitative measure, or a range or a category, of viable myocardium.For example, output unit 450, in one embodiment, outputs at least 20%increase of the second PEA over the first PEA or at least 20%reperfusion, or at least another percentage used as a metric ofreperfusion. It is apparent that medical practitioners will use outputunit 450 to output different useful outputs as needed and that suchoutputs could for example include ratios of the second PEA to the firstPEA or other mathematical functions describing a relationship betweenthe second PEA to the first PEA or vice versa.

The following applies to all embodiments based on reperfusion. Sincethere is no real baseline for the subject after a heart attack and thefirst PEA or the first MCI is used as the effective baseline formeasuring the amount of reperfusion, then in some embodiments there is apredefined mathematical relationship between the second PEA and thefirst PEA (or between the second MCI and the first MCI) that provides ametric for assessing that reperfusion has occurred to a defined extentor to a satisfactory extent or that provides a metric for assessing thatthrombolysis has been effective.

As shown in Tables 1-10 and FIG. 14, the trial that Applicant conductedon 27 subjects mimicked reperfusion. Applicant measured the PEA at thebeginning after 25 seconds of occlusion with a balloon and saw adecrease in PEA compared to a baseline, which means ischemia. ThenApplicant opened the balloon creating reperfusion. Applicant saw thatPEA returned immediately to baseline values. So one can usedifferentials in PEA to detect the amount of the return of blood to themyocardium (reperfusion) and the return of function, even though thesituation of a heart attack is somewhat different, since the principleis the same.

A further embodiment shown in FIG. 9AA is a method that parallels theapparatus 400 just described in regard to determining an amount ofre-perfusion. This embodiment is a method 800AA of non-invasivelydetermining an amount of reperfusion in a myocardium supplied by anartery of a mammalian subject after a heart attack of the mammaliansubject. Method 800AA may comprise a step 860 of, after a heart attackbut before opening the artery non-invasively sensing by a devicepositioned outside the subject mechanical vibrations that are from amechanical contraction of at least one of the ventricles of the heart ofthe mammalian subject, so as to measure a first peak endocardialacceleration (PEA) of the heart of the subject during an IVCT whereinIVCT is a time duration of an isovolumetric contraction portion of asystole phase of a cardiac cycle of the subject.

Method 800AA may also comprise as a step 870 of, after opening theartery after the heart attack, non-invasively sensing by a devicepositioned outside the subject mechanical vibrations that are from amechanical contraction of at least one of the ventricles of the heart ofthe mammalian subject, so as to measure a second peak endocardialacceleration (PEA) of the heart of the subject during an IVCT.

A further step 880 of method 800AA may be determining, by one or moreprocessors, an amount of reperfusion in the myocardium by comparing anamount by which the second PEA exceeds the first PEA. The determiningmay also include applying a mathematical function such as a percentageor a ratio or applying a range or a category to describe the amount ofreperfusion. The method 800AA may also include a step 890 of outputtingan alert or an output or conclusion of how much reperfusion occurred,how much restoration of function occurred derived from the opening ofthe artery, how much viable myocardium remains or any combinationthereof. Generally, the amount of reperfusion is proportionate to theamount of viable myocardium that exists in the subject.

The invention also includes embodiments that parallel the apparatus 400configured for determining an amount of reperfusion and method 800AA inwhich MCI is calculated from the PEA. For example, one embodiment of theinvention is a non-invasive apparatus 300 configured to non-invasivelydetermine an amount of reperfusion of blood to a myocardium supplied byan artery of a mammalian subject after a heart attack of the mammaliansubject, the apparatus 300 comprising: a sensor unit 310 configured tonon-invasively sense from outside the subject mechanical vibrations thatare from a mechanical contraction of at least one of the ventricles ofthe heart of the mammalian subject so as to simultaneously measure (a)IVCT, wherein IVCT is a time duration of an isovolumetric contractionportion of a systole phase of a cardiac cycle of the subject; and (b) apeak endocardial acceleration (PEA) of the heart of the subject duringthe IVCT. Apparatus 300 may also include a determination unit 344comprising one or more processors 340 programmed by software 340A storedon a memory 340B.

The determination unit 344 may be configured to receive digital signalscorresponding to the sensed mechanical vibrations, and to determine thePEA during the IVCT, the one or more processors configured to alsocalculate a first myocardial contractility index (MCI) of the subjectsuch that MCI comprises a ratio of the PEA of the subject to the IVCT ofthe subject, the determination unit 344 may include a perfusion modulefor determining, by the one or more processors 340 programmed by programcode 440A (for example software 440A), an amount of reperfusion in themyocardium by comparing a first MCI of the subject sensed by the sensorunit after a heart attack but before opening the artery to a second MCIof the subject sensed by the sensor unit at a subsequent time afteropening the artery. The perfusion module in one embodiment is part ofthe program code 340A executed by the one or more processors 340 of thedetermination unit 344.

The various types of outputs produced by an output unit 350 that may beincluded in apparatus 300 (for providing outputs relating to the amountof reperfusion), have already been described in connection with theoutput unit 450 of apparatus 400 (for providing outputs relating to theamount of reperfusion). The amount of reperfusion is in one embodimentconsidered proportionate to the amount of viable myocardium supplied bythe artery. Determination unit 344 may be configured to determine adegree of restoration of function of the subject's heart derived fromthe opening of the artery.

One embodiment of the invention is a method 700AA (as shown in FIG. 8AA)of non-invasively determining an amount of reperfusion in a myocardiumsupplied by an artery of a mammalian subject after a heart attack of themammalian subject. This method 700AA tracks method 800AA except that MCIis calculated from PEA. For example, method 700AA has a step 760 of,after a heart attack but before opening the artery non-invasivelysensing by a device positioned outside the subject mechanical vibrationsthat are from a mechanical contraction of at least one of the ventriclesof the heart of the mammalian subject, so as to simultaneously measure afirst IVCT, wherein IVCT is a time duration of an isovolumetriccontraction portion of a systole phase of a cardiac cycle of thesubject, and a first peak endocardial acceleration (PEA) of the heart ofthe subject during the first IVCT. A further step 770 of method 700AA iscalculating, by one or more processors, a first myocardial contractilityindex (MCI) of the subject, wherein the first MCI comprises a ratio ofthe first PEA of the subject to the first IVCT of the subject.

Method 700AA has another step 780 of, after opening the artery after theheart attack, non-invasively sensing by a device positioned outside thesubject mechanical vibrations that are from a mechanical contraction ofat least one of the ventricles of the heart of the mammalian subject, soas to simultaneously measure a second IVCT and a second peak endocardialacceleration (PEA) of the heart of the subject during the second IVCT.

A further step 790 of method 700AA is calculating, by one or moreprocessors, a second myocardial contractility index (MCI) of the subjectwherein the second MCI comprises a ratio of the second PEA of thesubject to the second IVCT of the subject; and determining, by one ormore processors, an amount of reperfusion in the myocardium, bycomparing an amount by which the second MCI exceeds the first MCI. It isunderstood that the amount of reperfusion is proportionate to a viablemyocardium supplied by the artery. Method 700AA may include a step 795of determining, by the one or more processors, a degree of restorationof function of the subject's heart derived from the opening of theartery. Optionally, there is a step 797 of outputting

In a further embodiment shown in FIG. 9, the invention is a method 800of determining an amount of viable or salvageable myocardium supplied byan artery of a mammalian subject after a heart attack of the mammaliansubject. Method 800 comprises in some embodiments a step 810 of during afirst sensing period after a heart attack but before opening the arterynon-invasively sensing, for example by a device positioned outside thesubject, mechanical vibrations that are from a mechanical contraction ofat least one of the ventricles of the heart of the mammalian subject, soas to measure a first peak endocardial acceleration (PEA) of the heartof the subject during an IVCT wherein IVCT is a time duration of anisovolumetric contraction portion of a systole phase of a cardiac cycleof the subject.

Method 800 in some embodiments has a further step 820 of, during asecond sensing period after opening the artery after the heart attack,non-invasively sensing, for example by a device positioned outside thesubject, mechanical vibrations that are from a mechanical contraction ofat least one of the ventricles of the heart of the mammalian subject, soas to measure a second peak endocardial acceleration (PEA) of the heartof the subject during an IVCT. Method 800 has a step 830 in someembodiments of determining, by a processor, an amount by which thesecond PEA exceeds the first PEA, said amount being proportionate to aviable myocardium supplied by the artery.

Apparatus 400, in a further embodiment, is configured to assess aneffectiveness of thrombolysis from an amount of reperfusion of blood. Inthis embodiment, a non-invasive apparatus 400 configured tonon-invasively assess an effectiveness of thrombolysis on a clot in anartery of a mammalian subject after a heart attack of the mammaliansubject by determining an amount of reperfusion in the artery, comprisesa sensor unit 410 configured to non-invasively sense from outside thesubject mechanical vibrations that are from a mechanical contraction ofat least one of the ventricles of the heart of the mammalian subject soas to simultaneously measure (a) IVCT, wherein IVCT is a time durationof an isovolumetric contraction portion of a systole phase of a cardiaccycle of the subject; and (b) a peak endocardial acceleration (PEA) ofthe heart of the subject during the IVCT. Apparatus 400 also comprises adetermination unit 444 comprising one or more processors 440 programmedby software 440A stored on a memory 440B. Determination unit 444 may beconfigured to receive digital signals corresponding to the sensedmechanical vibrations, and to determine the PEA during the IVCT.Determination unit 444 may include a perfusion module, which may be partof program code 440A, for determining, by one or more processors, anamount of reperfusion in the artery by comparing a first PEA of thesubject sensed by the sensor unit after a heart attack but before thethrombolysis to a second PEA of the subject sensed by the sensor unitafter the thrombolysis. Apparatus 400 may include an output unit 450that outputs an alert or a quantitative (or other) assessment of theeffectiveness of the thrombolysis in any form, including a differencebetween the first PEA and the second PEA in absolute amount orpercentage or a ratio or other function, as well as any category orrange describing the effectiveness (mildly effective moderatelyeffective, very effectiveness, almost completely effective, completelyeffective, effective to the following numerical amount etc.). The outputmay include for example that the PEA has increased by at least 20% or byat least some other pre-determined metric of effectiveness, or metric ora degree of effectiveness. Since the effectiveness of the thrombolysisis based on or proportionate to the amount of reperfusion in the arteryafter the thrombolysis as compared to before the thrombolysis, theoutput may also be in the form of an amount or percentage or other ratioof description of the reperfusion as described above in regard to otherreperfusion embodiments. The amount of reperfusion determines theassessment of the effectiveness of the thrombolysis. The determinationunit 444 may be configured to determine a degree of restoration offunction of the subject's heart derived from the thrombolysis in any ofthe above forms (an absolute amount, a percentage at least such and suchpercentage, at least 20%, or a grade or range or a category ofeffectiveness (moderately, partially, almost completely, completelyeffective, etc.).

As shown in FIG. 10AA, there is a method 900AA that parallels the justdescribed apparatus 400. Method 900AA is a method of non-invasivelyassessing an effectiveness of thrombolysis on a clot in an artery of amammalian subject after a heart attack of the mammalian subject bydetermining an amount of reperfusion in the artery. Method may comprisea step 960 of, after a heart attack but before thrombolysis,non-invasively sensing by a device positioned outside the subjectmechanical vibrations that are from a mechanical contraction of at leastone of the ventricles of the heart of the mammalian subject, so as tomeasure a first peak endocardial acceleration (PEA) of the heart of thesubject during an IVCT wherein IVCT is a time duration of anisovolumetric contraction portion of a systole phase of a cardiac cycleof the subject.

A further step 970 of method 900AA is, after the thrombolysis todissolve the clot, non-invasively sensing by a device positioned outsidethe subject mechanical vibrations that are from a mechanical contractionof at least one of the ventricles of the heart of the mammalian subject,so as to measure a second peak endocardial acceleration (PEA) of theheart of the subject during an IVCT.

Method 900AA may also comprise a step 980 of determining, by one or moreprocessors, an amount of reperfusion in the artery by comparing anamount by which the second PEA exceeds the first PEA. Method 900AA mayalso have a step 990 of outputting, using an output unit 350, an alertor a quantitative (or other) assessment of the effectiveness of thethrombolysis in any form, including a difference between the first PEAand the second PEA in absolute amount or percentage or a ratio or otherfunction, as well as any category or range describing the effectiveness(mildly effective moderately effective, very effectiveness, almostcompletely effective, completely effective, effective to the followingnumerical amount etc.). Since the effectiveness of the thrombolysis isbased on or proportionate to the amount of reperfusion in the arteryafter the thrombolysis as compared to before the thrombolysis, theoutput may be in the form of an amount or percentage or other ratio ofdescription of the reperfusion as described above in regard to otherreperfusion embodiments. Method 900AA may also include a step ofdetermining, by the one or more processors, a degree of restorationfunction of the subject's heart derived from the thrombolysis.

The following embodiment is of the apparatus 300 used for assessing theeffectiveness of thrombolysis based on the amount of reperfusion butwith the calculation of MCI. This tracks the description and details ofthe embodiment of apparatus 400 used for assessing the effectiveness ofthrombolysis based on the amount of reperfusion as described above basedon PEA (without MCI). To summarize, the embodiment is a non-invasiveapparatus 300 configured to non-invasively assess an effectiveness ofthrombolysis on a clot in an artery of a mammalian subject after a heartattack of the mammalian subject by determining an amount of reperfusionin the artery. The apparatus 300 may comprise a sensor unit 310configured to non-invasively sense from outside the subject mechanicalvibrations that are from a mechanical contraction of at least one of theventricles of the heart of the mammalian subject so as to simultaneouslymeasure (a) IVCT, wherein IVCT is a time duration of an isovolumetriccontraction portion of a systole phase of a cardiac cycle of thesubject; and (b) a peak endocardial acceleration (PEA) of the heart ofthe subject during the IVCT.

Apparatus 300 may comprise a determination unit 344 comprising one ormore processors 340 programmed by software 340A stored on a memory 340B,the determination unit 344 configured to receive digital signalscorresponding to the sensed mechanical vibrations, and to determine thePEA during the IVCT, the one or more processors 340 configured to alsocalculate a first myocardial contractility index (MCI) of the subjectsuch that MCI comprises a ratio of the PEA of the subject to the IVCT ofthe subject.

Determination unit 344 may include a perfusion module (which may be partof the software or program code 340A) for determining, by the one ormore processors 340, an amount of reperfusion in the artery by comparinga first MCI of the subject sensed by the sensor unit after a heartattack but before the thrombolysis to a second MCI of the subject sensedby the sensor unit after the thrombolysis. The output unit 350 outputs,an alert or a quantitative (or other) assessment of the effectiveness ofthe thrombolysis in any form, including a difference between the firstPEA and the second PEA in absolute amount or percentage or a ratio orother function, as well as any category or range describing theeffectiveness (mildly effective moderately effective, veryeffectiveness, almost completely effective, completely effective,effective to the following numerical amount etc.). Since theeffectiveness of the thrombolysis is based on or proportionate to theamount of reperfusion in the artery after the thrombolysis as comparedto before the thrombolysis, the output may be in the form of an amountor percentage or other ratio of description of the reperfusion asdescribed above in regard to other reperfusion embodiments. The outputmay also include a degree of restoration function of the subject's heartderived from the thrombolysis since the assessment of the effectivenessof the thrombolysis may be based on the amount of reperfusion.

The parallel method embodiment for assessing the effectiveness ofthrombolysis based on the amount of reperfusion using the calculation ofMCI is a method 1000AA (as shown in FIG. 11AA) of non-invasivelyassessing an effectiveness of thrombolysis on a clot, in an artery of amammalian subject after a heart attack of the mammalian subject bydetermining an amount of reperfusion in the artery. The method 1000AAmay comprise a step 1060 of, after a heart attack but beforethrombolysis, non-invasively sensing by a device positioned outside thesubject mechanical vibrations that are from a mechanical contraction ofat least one of the ventricles of the heart of the mammalian subject, soas to simultaneously measure a first IVCT, wherein IVCT is a timeduration of an isovolumetric contraction portion of a systole phase of acardiac cycle of the subject, and a first peak endocardial acceleration(PEA) of the heart of the subject during the first IVCT. The method1000AA may also comprise a step 1070 of calculating, by one or moreprocessors, a first myocardial contractility index (MCI) of the subject,wherein the first MCI comprises a ratio of the first PEA of the subjectto the first IVCT of the subject.

A further step 1080 of method 1000AA is, after the thrombolysis todissolve the clot, non-invasively sensing by a device positioned outsidethe subject mechanical vibrations that are from a mechanical contractionof at least one of the ventricles of the heart of the mammalian subject,so as to simultaneously measure a second IVCT and a second peakendocardial acceleration (PEA) of the heart of the subject during thesecond IVCT;

A still further step 1090 may comprise calculating, by one or moreprocessors, a second myocardial contractility index (MCI) of the subjectwherein the second MCI comprises a ratio of the second. PEA of thesubject to the second IVCT of the subject;

Method 1000AA may also include a step 1095 of determining, by one ormore processors, an amount of reperfusion in the artery by comparing anamount by which the second MCI exceeds the first MCI.

Method 1000AA may also have a step 1097 of outputting, using an outputunit 450, an alert or a quantitative (or other) assessment of theeffectiveness of the thrombolysis in any form, including a differencebetween the first MCI and the second MCI in absolute amount orpercentage or a ratio or other function, as well as any category orrange describing the effectiveness (mildly effective moderatelyeffective, very effectiveness, almost completely effective, completelyeffective, effective to the following numerical amount etc.). Since theeffectiveness of the thrombolysis is based on or proportionate to theamount of reperfusion in the artery after the thrombolysis as comparedto before the thrombolysis, the output may be in the form of an amountor percentage or other ratio of description of the reperfusion asdescribed above in regard to other reperfusion embodiments. Method1000AA may also include a step of determining, by the one or moreprocessors, a degree of restoration function of the subject's heartderived from the thrombolysis.

As shown in FIG. 10, the invention, in one further embodiment, is amethod 900 of determining an effectiveness of thrombolysis on a clot inan artery of a mammalian subject after a heart attack of the mammaliansubject. Method 900 in some embodiments has a step 910 of during a firstsensing period after a heart attack but before thrombolysisnon-invasively sensing, for example by a device positioned outside thesubject, mechanical vibrations that are from a mechanical contraction ofat least one of the ventricles of the heart of the mammalian subject, soas to measure a first peak endocardial acceleration (PEA) of the heartof the subject during an IVCT wherein IVCT is a time duration of anisovolumetric contraction portion of a systole phase of a cardiac cycleof the subject.

Method 900 has a step 920 in some embodiments of, during a secondsensing period after thrombolysis has been administered to dissolve theclot, non-invasively sensing mechanical vibrations that are from amechanical contraction of at least one of the ventricles of the heart ofthe mammalian subject, so as to measure a second peak endocardialacceleration (PEA) of the heart of the subject during an IVCT. Method900 has in some embodiments a step 930 of determining, by a processor,an amount by which the second PEA exceeds the first PEA, said amountdetermining the effectiveness of the thrombolysis. Note that method 900does not include the administration of the thrombolysis as a step of themethod. In some embodiments of method 900, the method includes a furtherstep of determining, by a processor, that the second PEA exceeded thefirst PEA by at least two-tenths (or by at least a certain fractionwherein the certain fraction is within the range between one-tenth andthree-tenths) so as to determine whether the thrombolysis has beeneffective (or in other embodiment determine how effective thethrombolysis has been).

As shown in FIG. 11, in a further embodiment, the invention is a method1000 of determining an effectiveness of thrombolysis on a clot in anartery of a mammalian subject after a heart attack of the mammaliansubject. Method 1000 has in some embodiments a step 1010 of during afirst sensing period after a heart attack but before thrombolysisnon-invasively sensing, for example by a device positioned outside thesubject, mechanical vibrations that are from a mechanical contraction ofat least one of the ventricles of the heart of the mammalian subject, soas to simultaneously measure (a) IVCT, wherein IVCT is a time durationof an isovolumetric contraction portion of a systole phase of a cardiaccycle of the subject; and (b) a peak endocardial acceleration (PEA) ofthe heart of the subject during the IVCT.

Method 1000 has a step 1020 in certain embodiments of calculating, byone or more processors, a first myocardial contractility index (MCI) ofthe subject, such that MCI comprises a ratio of the PEA of the subjectto the IVCT of the subject. In some examples this ratio isMCI=k·PEA/IVCT, where k is a constant. In one such embodiment, k=1, suchthat the ratio is MCI=PEA/IVCT.

In some embodiments, the calculation in step 120 is derived from signalscorresponding to the mechanical vibrations sensed during the firstsensing period.

Method 1000 in some embodiments has a step 1030 of during a secondsensing period after the thrombolysis non-invasively sensing, forexample by a device positioned outside the subject, mechanicalvibrations that are from a mechanical contraction of at least one of theventricles of the heart of the mammalian subject, so as tosimultaneously measure (a) a post-thrombolysis IVCT, wherein IVCT is atime duration of an isovolumetric contraction portion of a systole phaseof a cardiac cycle of the subject; and (b) a peak endocardialacceleration (PEA) of the heart of the subject during thepost-thrombolysis IVCT.

Method 1000 has a step 1040 in some embodiments of calculating, by theone or more processors, a second MCI of the subject for example fromsignals corresponding to the mechanical vibrations sensed during thesecond period. Method 1000 has a further step 1050 in some embodimentsof determining, by the one or more processors, an amount by which thesecond PEA exceeds the first PEA, said amount deter mining whether thethrombolysis has been effective (or in other embodiments determine howeffective the thrombolysis has been). In some embodiments, method 1000also has a step of determining that the second MCI exceeded the firstMCI by at least two-tenths (or by at least a certain fraction, whereinthe certain fraction is in a range between one tenth and three-tenths,for example 15% or 17% or 22% or 25%) so as to determine theeffectiveness of the thrombolysis.

A “processor” as used herein means a digital processor. In anyembodiment of the invention, PEA can be measured and/or outputted in anysuitable units of acceleration utilized by those skilled in the art, notjust dP/dtmax, for example G or milig.

In this patent application, the phrase “a ratio of the PEA of thesubject to the IVCT of the subject” or the “ratio of the PEA to theIVCT” of a subject or equivalent phrases are broad enough to include, atleast in some embodiments, a linear or non-linear function of PEA as asubstitute for PEA in the ratio and/or a linear or non-linear functionof IVCT as a substitute for IVCT in the ratio. The following deviationsfrom a simple ratio of PEA/IVCT are non-limiting, purely illustrative,examples that shall also be considered a ratio of the PEA to the IVCT ofthe subject: PEA/(IVCT plus c), where c is a constant; or (PEA+e)/IVCT,where c is a constant; or 2·PEA/IVCT; or PEA/(0.7·IVCT); or(2·PEA+c)/(0.7·IVCT−2c); or PEA^((1.5))/(IVCT^((0.8))+c) where c is aconstant.

While the invention has been described with respect to a limited numberof embodiments, it will be appreciated that many variations,modifications and other applications of the invention may be made.Therefore, the claimed invention as recited in the claims that follow isnot limited to the embodiments described herein.

What is claimed is:
 1. A non-invasive apparatus configured tonon-invasively determine an amount of reperfusion of blood to amyocardium supplied by an artery of a mammalian subject after a heartattack of the mammalian subject, the apparatus comprising: a sensor unitconfigured to non-invasively sense from outside the subject mechanicalvibrations that are from a mechanical contraction of at least one of theventricles of the heart of the mammalian subject so as to simultaneouslymeasure (a) IVCT, wherein IVCT is a time duration of an isovolumetriccontraction portion of a systole phase of a cardiac cycle of thesubject; and (b) a peak endocardial acceleration (PEA) of the heart ofthe subject during the IVCT; and a determination unit comprising one ormore processors programmed by software stored on a memory, thedetermination unit configured to receive digital signals correspondingto the sensed mechanical vibrations, and to determine the PEA during theIVCT, the determination unit including a perfusion module fordetermining, by the one or more processors, an amount of reperfusion inthe myocardium by comparing a first PEA of the subject sensed by thesensor unit after a heart attack but before opening the artery to asecond PEA of the subject sensed by the sensor unit at a subsequent timeafter opening the artery, said amount of reperfusion being proportionateto a viable myocardium supplied by the artery.
 2. The apparatus of claim1, wherein the determination unit is configured to determine a degree ofrestoration of function of the subject's heart derived from the openingof the artery.
 3. A method of non-invasively determining an amount ofreperfusion in a myocardium supplied by an artery of a mammalian subjectafter a heart attack of the mammalian subject, comprising: after a heartattack but before opening the artery non-invasively sensing by a devicepositioned outside the subject mechanical vibrations that are from amechanical contraction of at least one of the ventricles of the heart ofthe mammalian subject, so as to measure a first peak endocardialacceleration (PEA) of the heart of the subject during an IVCT whereinIVCT is a time duration of an isovolumetric contraction portion of asystole phase of a cardiac cycle of the subject; after opening theartery after the heart attack, non-invasively sensing by a devicepositioned outside the subject mechanical vibrations that are from amechanical contraction of at least one of the ventricles of the heart ofthe mammalian subject, so as to measure a second peak endocardialacceleration (PEA) of the heart of the subject during an IVCT; anddetermining, by one or more processors, an amount of reperfusion in themyocardium by comparing an amount by which the second PEA exceeds thefirst PEA, said amount of reperfusion being proportionate to a viablemyocardium supplied by the artery.
 4. The method of claim 3, furthercomprising determining, by the one or more processors, a degree ofrestoration of function of the subject's heart derived from the openingof the artery.
 5. A non-invasive apparatus configured to non-invasivelydetermine an amount of reperfusion of blood to a myocardium supplied byan artery of a mammalian subject after a heart attack of the mammaliansubject, the apparatus comprising: a sensor unit configured tonon-invasively sense from outside the subject mechanical vibrations thatare from a mechanical contraction of at least one of the ventricles ofthe heart of the mammalian subject so as to simultaneously measure (a)IVCT, wherein IVCT is a time duration of an isovolumetric contractionportion of a systole phase of a cardiac cycle of the subject; and (b) apeak endocardial acceleration (PEA) of the heart of the subject duringthe IVCT; and a determination unit comprising one or more processorsprogrammed by software stored on a memory, the determination unitconfigured to receive digital signals corresponding to the sensedmechanical vibrations, and to determine the PEA during the IVCT, the oneor more processors configured to also calculate a first myocardialcontractility index (MCI) of the subject such that MCI comprises a ratioof the PEA of the subject to the IVCT of the subject; the determinationunit including a perfusion module for determining, by the one or moreprocessors, an amount of reperfusion in the myocardium by comparing afirst MCI of the subject sensed by the sensor unit after a heart attackbut before opening the artery to a second MCI of the subject sensed bythe sensor unit at a subsequent time after opening the artery, saidamount of reperfusion being proportionate to a viable myocardiumsupplied by the artery.
 6. The apparatus of claim 5, wherein thedetermination unit is configured to determine a degree of restoration offunction of the subject's heart derived from the opening of the artery.7. A method of non-invasively determining an amount of reperfusion in amyocardium supplied by an artery of a mammalian subject after a heartattack of the mammalian subject, comprising: after a heart attack butbefore opening the artery non-invasively sensing by a device positionedoutside the subject mechanical vibrations that are from a mechanicalcontraction of at least one of the ventricles of the heart of themammalian subject, so as to simultaneously measure a first IVCT, whereinIVCT is a time duration of an isovolumetric contraction portion of asystole phase of a cardiac cycle of the subject, and a first peakendocardial acceleration (PEA) of the heart of the subject during thefirst IVCT; calculating, by one or more processors, a first myocardialcontractility index (MCI) of the subject, wherein the first MCIcomprises a ratio of the first PEA of the subject to the first IVCT ofthe subject; after opening the artery after the heart attack,non-invasively sensing by a device positioned outside the subjectmechanical vibrations that are from a mechanical contraction of at leastone of the ventricles of the heart of the mammalian subject, so as tosimultaneously measure a second IVCT and a second peak endocardialacceleration (PEA) of the heart of the subject during the second IVCT;calculating, by one or more processors, a second myocardialcontractility index (MCI) of the subject wherein the second MCIcomprises a ratio of the second PEA of the subject to the second IVCT ofthe subject; and determining, by one or more processors, an amount ofreperfusion in the myocardium, by comparing an amount by which thesecond MCI exceeds the first MCI, said amount of reperfusion beingproportionate to a viable myocardium supplied by the artery.
 8. Themethod of claim 7, further comprising determining, by the one or moreprocessors, a degree of restoration of function of the subject's heartderived from the opening of the artery.
 9. A non-invasive apparatusconfigured to non-invasively assess an effectiveness of thrombolysis ona clot in an artery of a mammalian subject after a heart attack of themammalian subject by determining an amount of reperfusion in the artery,the apparatus comprising: a sensor unit configured to non-invasivelysense from outside the subject mechanical vibrations that are from amechanical contraction of at least one of the ventricles of the heart ofthe mammalian subject so as to simultaneously measure (a) IVCT, whereinIVCT is a time duration of an isovolumetric contraction portion of asystole phase of a cardiac cycle of the subject; and (b) a peakendocardial acceleration (PEA) of the heart of the subject during theIVCT; and a determination unit comprising one or more processorsprogrammed by software stored on a memory, the determination unitconfigured to receive digital signals corresponding to the sensedmechanical vibrations, and to determine the PEA during the IVCT, thedetermination unit including a perfusion module for determining, by theone or more processors, an amount of reperfusion in the artery bycomparing a first PEA of the subject sensed by the sensor unit after aheart attack but before the thrombolysis to a second PEA of the subjectsensed by the sensor unit after the thrombolysis, said amount ofreperfusion determining an assessment of the effectiveness of thethrombolysis.
 10. The apparatus of claim 9, wherein the determinationunit is configured to determine a degree of restoration of function ofthe subject's heart derived from the thrombolysis.
 11. A method ofnon-invasively assessing an effectiveness of thrombolysis on a clot inan artery of a mammalian subject after a heart attack of the mammaliansubject by determining an amount of reperfusion in the artery,comprising: after a heart attack but before thrombolysis, non-invasivelysensing by a device positioned outside the subject mechanical vibrationsthat are from a mechanical contraction of at least one of the ventriclesof the heart of the mammalian subject, so as to measure a first peakendocardial acceleration (PEA) of the heart of the subject during anIVCT wherein IVCT is a time duration of an isovolumetric contractionportion of a systole phase of a cardiac cycle of the subject; after thethrombolysis to dissolve the clot, non-invasively sensing by a devicepositioned outside the subject mechanical vibrations that are from amechanical contraction of at least one of the ventricles of the heart ofthe mammalian subject, so as to measure a second peak endocardialacceleration (PEA) of the heart of the subject during an IVCT; anddetermining, by one or more processors, an amount of reperfusion in theartery by comparing an amount by which the second PEA exceeds the firstPEA, said amount of reperfusion determining an assessment of theeffectiveness of the thrombolysis.
 12. The method of claim 11, furthercomprising determining by the one or more processors, a degree ofrestoration function of the subject's heart derived from thethrombolysis.
 13. A non-invasive apparatus configured to non-invasivelyassess an effectiveness of thrombolysis on a clot in an artery of amammalian subject after a heart attack of the mammalian subject bydetermining an amount of reperfusion in the artery, the apparatuscomprising: a sensor unit configured to non-invasively sense fromoutside the subject mechanical vibrations that are from a mechanicalcontraction of at least one of the ventricles of the heart of themammalian subject so as to simultaneously measure (a) IVCT, wherein IVCTis a time duration of an isovolumetric contraction portion of a systolephase of a cardiac cycle of the subject; and (b) a peak endocardialacceleration (PEA) of the heart of the subject during the IVCT; and adetermination unit comprising one or more processors programmed bysoftware stored on a memory, the determination unit configured toreceive digital signals corresponding to the sensed mechanicalvibrations, and to determine the PEA during the IVCT, the one or moreprocessors configured to also calculate a first myocardial contractilityindex (MCI) of the subject such that MCI comprises a ratio of the PEA ofthe subject to the IVCT of the subject; the determination unit includinga perfusion module for determining, by the one or more processors, anamount of reperfusion in the artery by comparing a first MCI of thesubject sensed by the sensor unit after a heart attack but before thethrombolysis to a second MCI of the subject sensed by the sensor unitafter the thrombolysis, said amount of reperfusion determining anassessment of the effectiveness of the thrombolysis.
 14. The apparatusof claim 13, wherein the determination unit is configured to determine adegree of restoration of function of the subject's heart derived fromthe thrombolysis.
 15. A method of non-invasively assessing aneffectiveness of thrombolysis on a clot in an artery of a mammaliansubject after a heart attack of the mammalian subject by determining anamount of reperfusion in the artery, comprising: after a heart attackbut before thrombolysis, non-invasively sensing by a device positionedoutside the subject mechanical vibrations that are from a mechanicalcontraction of at least one of the ventricles of the heart of themammalian subject, so as to simultaneously measure a first IVCT, whereinIVCT is a time duration of an isovolumetric contraction portion of asystole phase of a cardiac cycle of the subject, and a first peakendocardial acceleration (PEA) of the heart of the subject during thefirst IVCT; calculating, by one or more processors, a first myocardialcontractility index (MCI) of the subject, wherein the first MCIcomprises a ratio of the first PEA of the subject to the first IVCT ofthe subject; after the thrombolysis to dissolve the clot, non-invasivelysensing by a device positioned outside the subject mechanical vibrationsthat are from a mechanical contraction of at least one of the ventriclesof the heart of the mammalian subject, so as to simultaneously measure asecond IVCT and a second peak endocardial acceleration (PEA) of theheart of the subject during the second IVCT; calculating, by one or moreprocessors, a second myocardial contractility index (MCI) of the subjectwherein the second MCI comprises a ratio of the second PEA of thesubject to the second IVCT of the subject; and determining, by one ormore processors, an amount of reperfusion in the artery by comparing anamount by which the second MCI exceeds the first MCI, said amount ofreperfusion determining an assessment of the effectiveness of thethrombolysis.
 16. The apparatus of claim 11, further comprisingdetermining, by the one or more processors, a degree of restorationfunction of the subject's heart derived from the thrombolysis.